A quantitative threshold for high/ low extent of urinary excretion of compounds in humans

Abstract

In this study, we determined a quantitative threshold for high/ low extent of urinary excretion (UE) of compounds in humans, using a straightforward but robust statistical method known as receiver operating characteristic curve (ROC) analysis, and also evaluated 18 potential physicochemical determinants of UE. Data on the percent of drug excreted unchanged into the urine, %A_e, was used to determine the threshold for high/ low UE. Compounds can be divided into high/ low UE groups using the threshold value of A_e = 16.8%, namely those with A_e >16.8% classified as high UE and those with A_e ≤16.8% as low UE. %A_e negatively correlated with cLogP (r=−0.56); however, cLogP could not quantitatively predict the value of %A_e (R²_adj.=0.32). Several determinants of the extent of UE, including cLogP, ACD labs cLogP, and ACD labs cLogD_(pH=7.4), were successfully evaluated as priori indicators of the extent of UE using two cut-off values for each parameter. Moreover, 87% of 90 compounds in the external validation set were correctly classified using this approach. Analysis of the physicochemical spaces of compounds in these two groups showed significant overlap, which hinders a priori determination of extent of UE of compounds using single threshold/ cut-off value of simple physicochemical parameters. In conclusion, 16.8% is a quantitative threshold value to distinguish between high and low UE and new molecular entities with cLogP and ACD labs cLogP values of ≤0.7 and ≥1.0 and ACD labs cLogD_(pH=7.4) values of ≤0.0 and ≥0.5 could be identified as exhibiting high and low UE, respectively.

INTRODUCTION

Urinary excretion (UE) is a major route of elimination for drugs and drug-metabolites with poor metabolism and biliary excretion [1, 2]. In this manuscript, we introduce a quantitative threshold to distinguish between compounds with high and low extent of UE and further evaluate several physicochemical indicators of UE in humans.

In the past two decades, Biopharmaceutics Drug Classification System [3], Lipinski’s Rule of 5 [4], and Biopharmaceutics Drug Disposition Classification System (BDDCS) [5] have revolutionized contemporary drug discovery and development [6]. When BDDCS was applied to 927 marketed drugs, drugs undergoing poor metabolism had greater values for percent of drug excreted unchanged into the urine (%A_e) than drugs undergoing extensive metabolism [7]. However, statistical analysis was not performed on %A_e data in this study.

To our best knowledge, guidelines that 1) propose a quantitative threshold for high/ low extent of UE of compounds and 2) exclusively evaluate the physicochemical indicators of the extent of UE such as cLogP, LogD, or polar surface area (PSA) have not been reported. A quantitative threshold for high/ low extent of UE would contribute significantly to identify the UE of new molecular entities (NMEs) during drug discovery and development. In this research, we used receiver operating characteristic (ROC) curve analysis, a robust statistical method that is used traditionally in medical diagnostic tests to determine a threshold value with high sensitivity and specificity while minimizing the occurrence of false positive and false negative predictions [8–10]. Our laboratory has previously demonstrated the use of ROC curve analysis to determine a quantitative molecular weight threshold for compounds undergoing biliary excretion in rats, dogs, and humans [11, 12].

The objectives of this study were to: 1) determine a quantitative threshold value to distinguish between compounds undergoing low and high UE, and 2) assess potential physiochemical indicators of extent of UE in humans.

MATERIALS AND METHODS

Data acquisition and processing

We utilized data on percent of drug excreted unchanged into urine (%A_e) (N = 834) and associated information on BDDCS classification in humans. (1) measured LogP (MLogP) and (2) measured LogD_(pH=7.4) (MLogD) were obtained from Benet et al. [7]. We further obtained (3) calculated LogP (cLogP), and (4) polar surface area (PSA), (5) ACD labs cLogP, (6) ACD labs cLogD_(pH=7.4), (7) pKa, (8) ionization status (anions, cations, zwitterions, and neutral) at pH of 7.4, (9) water accessible surface area, (10) polarizability, (11) molar refractivity, (12) molecular volume, (13) molecular weight, (14) # free rotatable bonds, (15) # of rings, (16) dreiding energy, (17) minimum projection area, and (18) maximum projection areas for all compounds from ChemSpider search and share chemistry online database [13] and ChEMBL database [14]. ‘cLogP’ descriptor values (#3) obtained from the ChemSpider and CheMBL databases were calculated using ChemAxon physicochemical properties calculator program. We evaluated two cLogP descriptors (calculated using two different programs) because ACD labs cLogP is very widely accepted and ChemAxon cLogP, herein referred as cLogP, is more readily available. The complete listing of 834 compounds is given in table 1.

Table 1.

Listing of BDDCS classes, %A_e, cLogP, ACD labs cLogP, and ACD labs cLogD (pH=7.4) of 834 compounds.

Generic Name	BDDCS Class	% UE	cLogP	ACD cLogP	ACD cLogD (pH=7.4)
10-Hydroxy- Carbamazepine	2	27	1.21	0.93	1.41
6-Methoxy-2-Naphthyl- Acetic Acid	2	1	2.51	2.65	−0.03
Abacavir Sulfate	1	1.2	0.81	1.16	1.16
Acamprosaic Acid	3	50	−2.47	−2.47	−2.47
Acarbose	1	1	−6.66	−4.16	−4.76
Acebutolol Hydrochloride	1	10	1.71	1.77	−3
Acecainide; N-Acetyl Procainamide	3	81	1.64	1.29	−0.56
Acetaminophen; Paracetamol	1	3	0.49	1.08	0.74
Acetazolamide	4	90	−0.98	−0.26	−0.81
Acetylsalicylic Acid; Aspirin	1	1.4	1.02	1.19	−1.69
Acitretin	2	0	6.07	5.73	2.71
Acrivastine	3	67	1.46	4.55	0.99
Acyclovir	4	75	−2.42	−3.31	−4.64
Adefovir Dipivoxil	3	45	−1.98	2.45	2.2
Adenosine	1	0	−2.16	−1.02	−0.99
Albendazole	2	0	3.46	3.07	3.1
Albendazole Sulfoxide	2	1	3.46	0.91	1.26
Albuterol; Salbutamol	3	50	0.06	0.01	−1.52
Alendronate Sodium	3	45	−5.64	−0.73	−5.12
Alfacalcidol	1	8	8.24	8.31	7.58
Alfentanil	1	0.5	2.13	1.99	1.69
Alfuzosin	1	11	2.55	−1	0.1
Aliskiren	1	25	3.51	2.74	0.26
Allopurinol	2	12	0.63	−1.46	−2.02
Almotriptan	3	40	1.79	1.88	0.3
Alosetron	1	6	1.74	0.88	1.74
Alprazolam	1	20	2.56	2.5	2.63
Alprenolol	1	0.5	2.65	2.88	0.68
Altretamine	2	0.5	1.67	2.42	2.47
Alvimopan	3	2	2.16	3.38	0.55
Amantadine	3	85	2	1.01	−3.24
Ambrisentan	1	5	3.33	2.82	−0.92
Ambroxol	1	8	2.66	2.91	1.31
Amifostine	1	0.69	−1.85	−1.68	−4.35
Amikacin	3	98	−6.3	−2.85	−9.52
Amiloride	3	49	0.11	3.05	−0.92
Aminocaproic Acid	3	65	−2.24	−0.11	−3.45
Amiodarone Hydrochloride	2	0	8.95	7.82	5.87
Amisulpride	4	50	1.8	1.6	−0.43
Amitriptyline Hydrochloride	1	1	4.85	4.41	2.65
Amlodipine	1	10	3.43	4.16	1.91
Amoxicillin	3	86	−1.87	0.92	−3.02
Amphetamine Sulfate	0	40	1.74	7.79	−0.65
Amphotericin B	2	3.5	−3.65	1.16	−2.24
Ampicillin	3	88	−1.2	1.65	−2.57
Amprenavir	2	1	3.29	4.68	2.92
Amsacrine	1	10	4.69	2.12	3.1
Anastrozole	1	10	1.29	0.97	2.68
Anhydrovinblastine; Anhydrovincaleukoblastine	1	0.5	6.11	5.31	4.94
Anidulafungin	2	0.5	2.2	−3.86	−2.33
Antipyrine; Phenazone	1	0.5	0.2	0.27	0.72
Apomorphine	1	0.3	2.49	3.05	2.52
Aprepitant	2	0	4.6	4.99	4.84
Argatroban	2	16	−0.57	−0.16	−2.34
Aripiprazole	2	0.5	5.31	5.59	4.99
Armodafinil	2	8	0.94	1.17	1.37
Asenapine	1	1	4.58	4.31	1.82
Astemizole	2	0.5	6.09	5.8	4.24
Atazanavir Sulfate	2	7	5.92	3.17	1.8
Atenolol	3	94	−0.11	0.1	−1.85
Atomoxetine	1	1.5	3.94	3.28	1.06
Atorvastatin Calcium	2	1	4.46	2.68	2.68
Atovaquone	4	3	6.35	6.18	2.49
Atracurium	0	8.5	3.5	1.04	−1.37
Atropine (DL)	3	57	1.3	1.53	−0.61
Auranofin	4	60	3.79	3.8	3.82
Azacitidine	3	62	−2.2	−1.99	−2.3
Azapropazone; Apazone	4	60	1.79	1.72	1.57
Azathioprine	1	1	0.51	0.67	−0.04
Azelastine Hydrochloride	2	2	4.01	3.17	1.57
Azithromycin	3	6	2.64	3.33	1.36
Azlocillin	3	65	1.56	−0.34	−3.19
Aztreonam	3	68	0.34	−0.66	−6.02
Baclofen	3	69	−0.62	1.56	−0.94
Bambuterol	1	0	0.56	0.5	−0.6
Benazepril	1	0.5	1.82	3.86	−0.71
Benazeprilat	3	18	2.04	2.98	−1.76
Bendamustine	1	1	2.76	2.69	0.26
Bendroflumethiazide	3	21	1.73	2.07	1.46
Benidipine	1	1	7.41	4.92	4.34
Benserazide	1	1	−2.9	−2.03	−2.01
Bepridil	1	0.5	6.2	5.8	3.4
Betamethasone	1	4.8	1.79	1.87	1.92
Betamipron	3	98	0.72	0.67	−2.47
Betaxolol	1	15	2.32	2.69	0.76
Bevantolol	2	8	3	3.38	1.07
Bexarotene	2	0.01	8.19	8.55	4.91
Bezafibrate	2	40	3.7	3.46	−0.11
Biapenem	3	53	−6.35	−6.14	−5.54
Biotin	3	43	−0.08	0.03	−3
Bisoprolol Fumarate	3	63	1.83	5.6	5.6
Bleomycin A2	3	68	−7.68	−7.68	−7.68
Bopindolol	1	0	4.98	4.9	2.81
Bosentan	2	2	4.17	1.15	1.53
Bretylium	3	77	−1.25	−1.17	−1.37
Brimonidine	1	10	1.49	0.96	0.7
Bromocriptine	1	2	6.58	6.11	3.41
Bromperidol	1	0.5	4	3.19	2.66
Budesonide	1	0	2.91	3.14	3.02
Buflomedil Hydrochloride	1	23.6	2.93	1.2	1.24
Bumetanide	3	45	3.37	2.78	0.03
Bupivacaine	1	2	3.69	3.64	2.68
Buprenorphine Hydrochloride	1	1	3.99	3.84	−0.66
Bupropion	1	0.5	3.21	3.47	2.88
Buspirone	2	0.1	2.19	3.43	2.6
Busulfan (Busulphan)	1	1	−0.59	−0.52	−0.42
Butabarbital	1	1	1.58	1.52	1.32
Butalbital	1	3.6	1.63	1.49	−3.03
Butorphanol	1	2	3.73	3.77	2.75
Cabergoline	2	3	4.77	2.43	1.49
Cadralazine	3	75	0.93	0.54	0.43
Caffeine	1	1	−0.04	−0.13	0.28
Calcipotriene; Calcipotriol	2	0.5	5.27	5.43	5.03
Calcitriol	2	8	6.04	6.12	5.63
Candesartan	4	52	5.43	5.02	0.09
Candesartan Cilexetil	4	0	7.33	7.79	4.03
Capecitabine	1	3	0.84	1.61	−2.13
Capreomycin 1b	3	90	−5.51	−9.89	−14.44
Caprylidene	1	0	9.97	9.33	9.55
Capsaicin	2	0	4	4.27	2.43
Captopril	3	38	0.89	0.27	−2.83
Carbamazepine	2	0.5	2.38	2.67	2.28
Carbamazepine 10,11- Epoxide	2	0.5	0.24	1.26	1.31
Carbenicillin	3	82	1.64	1.01	−3.24
Carbidopa	1	5.3	−0.45	−0.19	−2.58
Carboplatin	3	77	−0.34	−0.34	−0.34
Carmustine	1	0.5	1.32	1.3	1.67
Carteolol	3	60	1.29	1.35	−0.24
Carvedilol	2	1	4.04	4.11	3.04
Caspofungin Acetate	1	1.4	−2.95	−2.95	−2.95
Cefaclor	3	52	−1.64	0.1	−3.63
Cefadroxil	3	93	−2.51	−0.09	−4.06
Cefamandole	3	96	0.11	1.52	−3.35
Cefazolin	3	80	−1.19	1.13	−4.02
Cefdinir	4	15	−0.48	−1.78	−5.48
Cefditoren	4	70	1.46	1.48	−2.82
Cefditoren Pivoxil	2	5	2.71	2.74	2.37
Cefepime	3	85	−3.05	−1.62	−2.52
Cefixime	4	41	0.25	1	−4.59
Cefmetazole Sodium	3	80	−1.34	2.97	2.53
Cefodizime	3	80	1.1	2.55	−3.18
Cefonicid	3	99	−1.92	−0.45	−6.45
Cefoperazone	1	29	−0.22	1.43	−3.61
Ceforanide	3	84	−3.36	0.6	−3.85
Cefotaxime	3	30	0.14	1.2	−3.35
Cefotetan	3	67	−1.54	2.34	−5.05
Cefotiam	3	80	−3.58	0.24	−2.9
Cefoxitin	3	85	−0.81	0.63	−3.45
Cefpodoxime	4	81	−0.41	0.94	−3.33
Cefpodoxime Proxetil	2	0	0.8	2.17	1.36
Cefprozil	4	73	−1.87	0.06	−3.79
Cefsulodin	3	60	−6.89	−5.25	−6.12
Ceftazidime	3	85	−3.75	−2.84	−3.21
Ceftibuten	4	71	−1.21	−0.96	−5.79
Ceftizoxime	3	93	0.34	0.59	−3.61
Ceftriaxone	3	46	0.02	−0.77	−4.51
Cefuroxime	3	96	0.23	0.42	−4.4
Celecoxib	2	2	4.37	4.21	3.23
Celiprolol	3	20	1.86	1.92	−0.07
Cephalexin	3	91	−1.84	0.65	−3.63
Cephalothin Sodium	3	52	−0.28	−0.37	−0.37
Cephapirin	3	48	−0.61	0.79	−3.79
Cephradine	3	86	−1.73	0.98	−3.45
Cerivastatin	1	24	3.56	3.7	0.59
Cetirizine	3	50	2.08	2.16	−0.55
Cetrorelix	1	3	−0.4	2.69	−1.53
Cevimeline	1	13.5	1.14	1.23	−0.44
Chlorambucil	1	0.5	3.63	3.1	0.56
Chloramphenicol	1	5	1.28	1.62	0.52
Chlordiazepoxide	1	0.5	3.79	1.11	2.33
Chlormethiazole; Clomethiazole	1	0.05	1.68	1.56	2.21
Chloroquine	3	61	5.06	4.69	1.74
Chlorothiazide	4	92	−1	−0.18	−0.21
Chlorpheniramine	1	10	3.15	3.39	1.16
Chlorphentermine	0	17	2.85	2.75	0.3
Chlorpromazine	1	0.5	5.3	5.2	3.42
Chlorpropamide	0	20	2.35	2.8	0.05
Chlorthalidone	4	65	0.45	−0.74	0.41
Chlorzoxazone	2	0.5	2.51	2.29	−1.19
Ciclesonide	2	0	5.25	5.12	4.92
Cidofovir	3	90	−2.39	−3.37	−7.35
Cilastatin	3	70	0.47	2.92	−2.1
Cilazapril	1	0	1.47	0.73	−2.49
Cilazaprilat	3	91	1.5	−0.15	−3.41
Cimetidine	3	62	0.19	0.07	0.37
Cinacalcet	2	0.1	6.35	5.74	4.03
Cinoxacin	4	60	1.74	0.35	−2.87
Ciprofloxacin	4	65	−0.73	0.65	−2.23
Cisatracurium Besylate	0	8.5	3.5	−0.12	−2.63
Cisplatin	1	2.3	−1.68	−1.7	−1.74
Citalopram	2	12	3.13	2.51	1.27
Cladribine	2	18	−0.91	0.02	0.01
Clarithromycin	3	35	2.37	3.16	2.38
Clavulanic Acid	3	43	−1.07	−1.98	−4.72
Clemastine	1	5	5.45	5.69	3.22
Clindamycin Hydrochloride Hydrate	1	13	2.57	3.4	3.06
Clodronic Acid	4	80	−0.14	−2.38	−8.29
Clofarabine	3	55	−0.46	0.24	−0.17
Clofazimine	2	0.2	7.7	7.26	5.78
Clofibrate	2	11	3.02	3.32	3.53
Clofibric Acid	1	5.7	2.82	2.72	−0.88
Clomiphene Citrate	1	8	7.15	8.01	4.95
Clonazepam	1	0.5	2.38	2.34	2.53
Clonidine	3	62	1.73	1.41	1.04
Clorazepate	1	0.5	2.51	2.9	−1.17
Clotrimazole	2	5	5.25	5.44	5.22
Cloxacillin	4	75	2.52	2.53	−1.21
Clozapine	2	0.5	3.71	2.36	2.72
Cocaine	1	1	2.57	3.08	1.22
Codeine Monohydrate	1	0.1	0.98	1.39	0.46
Conivaptan Hydrochloride	2	1	5	3.72	3.72
Cromolyn	3	50	1.48	2.3	−2.95
Cyanocobalamin (Vitamin B12)	1	0.5	−1.36	−1.36	−1.36
Cyclizine	1	0.5	3.8	2.41	2.4
Cyclobenzaprine	1	0.5	5.1	5	2.89
Cyclophosphamide	1	6.5	0.8	0.23	0.53
Cycloserine	3	65	−1.19	−1.84	−1.85
Cyclosporine	2	0.1	14.36	3.35	1.8
Cyproheptadine	1	0.5	5.3	6.41	3.51
Cyproterone Acetate	2	1	3.96	3.28	3.62
Cytarabine	1	11	−2.2	−1.78	−4.38
Dabigatran	3	85	0.06	0.79	−1.08
Dabigatran Etexilate	1	0	4.13	5.13	4.72
Dacarbazine	3	39	0.48	−0.28	0.08
Dactinomycin (Actinomycin D)	3	10	8.01	−4.03	−2.39
Dalfampridine	3	90.3	0.32	−2.24	−2.41
Dalfopristin	4	4.5	0.92	−0.76	−1.42
Dantrolene	1	5	1.63	0.71	−1.79
Dapsone	2	15	0.89	0.94	1.08
Daptomycin	3	40.5	−2.43	−4.07	−9.72
Darifenacin	1	12.5	3.62	4.5	2.33
Darunavir	2	1.2	2.89	3.94	3.09
Dasatinib	2	0.1	2.88	2.24	2.17
Daunorubicin	2	0.5	0.84	2.92	−0.29
Daunorubicinol	4	25	1.36	2.98	0.4
Debrisoquine	1	12	0.9	0.14	−1.13
Delavirdine	2	2.5	2.41	−1.21	0.78
Demeclocycline	3	47	−0.59	−1.07	−3.4
Desalkylflurazepam	1	0.5	2.81	2.4	2.46
Desipramine	1	2	4.47	4.13	1.58
Desloratadine	2	5	3.83	6.77	2.14
Desmethyldiazepam (Nordazepam)	1	0.5	3.02	2.54	2.53
Desmopressin	3	47	−3.14	−5.82	−7.34
Desogestrel	1	0	5.68	6.59	5.92
Desvenlafaxine	3	45	2.68	2.26	0.89
Dexamethasone	1	2.6	1.79	1.87	1.92
Dexmethylphenidate	1	0.5	2.56	2.55	0.26
Dexrazoxane	3	42	−1.33	−0.37	−0.83
Dextroamphetamine	0	40	1.74	1.81	−0.62
Dextromethorphan Hydrobromide	1	0.19	3.95	3.89	2.17
Dezocine	1	1	3.72	3.95	1.01
Diazepam	1	0.5	2.96	2.91	2.92
Diazoxide	2	35	1.42	1.08	1.23
Dibekacin; Dideoxykanamycin B	3	81	−3.41	−3.23	−9.3
Diclofenac	1	0.5	4.73	4.06	1.37
Dicloxacillin	3	60	2.98	3.02	−0.65
Dicoumarol	2	0.5	3.66	3.55	−0.62
Didanosine	3	55	−1.65	−1.31	−3.68
Diethylcarbamazine Citrate	0	35	1.62	1.66	1.5
Diflunisal	2	6	4.4	4.44	1.16
Digitoxin	3	30	2.85	2.44	2.42
Digoxin	3	60	1.42	0.85	1.26
Dihydroquinidine; Hydroquinidine	1	18	3.27	3.77	1.02
Dilevalol	1	2.5	2.5	2.31	0.85
Diloxanide Furoate	2	1	3.09	1.42	2.34
Diltiazem	1	2	3.65	3.63	2.06
Diphenhydramine	1	2	3.45	3.66	2.34
Dipyridamole	2	0.1	1.49	−1.22	0.3
Disopyramide	3	55	2.58	2.86	0.35
Disulfiram	2	0	3.88	3.88	3.59
Dobutamine Hydrochloride	1	0.1	2.43	2.53	0.02
Docetaxel	2	5	4.08	6.55	3.54
Dofetilide	3	64	1.99	1.56	0.83
Dolasetron	1	0	2.34	2.82	2.63
Domperidone	2	0	4.27	4.63	0.76
Donepezil	2	10.6	4.6	4.71	2.79
Dorzolamide Hydrochloride	3	10	−0.43	1.67	1.53
Dosulepin; Dothiepin	1	5	4.53	4.34	2.92
Doxepin	1	0	4.09	3.86	2.5
Doxorubicin	1	3.5	0.32	2.82	−0.79
Doxycycline	3	41	−0.51	−0.54	−3.29
Dronabinol; Tetrahydrocannabinol	2	0.5	7.24	7.68	7.25
Dronedarone	2	0	8.57	7.58	3.98
Drospirenone	2	0.1	2.84	3.15	3.46
Duloxetine Hydrochloride	1	0	4.26	4.81	2.31
Dutasteride	2	0.5	4.94	5.93	5.93
Ebastine	2	2	6.94	7.79	6.32
Edetate Calcium Disodium	3	95	−1.93	−1.93	−1.93
Efavirenz	2	0.5	4.67	3.72	2.43
Eletriptan Hydrobromide	1	5	3.36	1.96	1.96
Emtricitabine	3	73	−1.29	−0.41	−0.73
Enalapril	1	10	0.67	2.43	−1.57
Enalaprilat	3	60	0.88	1.54	−2.68
Enfuvirtide	1	0	11	11	11
Enoxacin	4	45	−1.6	0.55	−2.84
Entacapone	2	0.2	1.76	2.38	−0.04
Entecavir	3	70	−2.58	−0.96	−0.81
Epirubicin	1	9.5	0.32	2.82	−0.79
Eplerenone	2	3	0.29	1.05	1.66
Eprosartan	4	30	4.8	4.96	1.09
Eptifibatide	3	50	−2.86	−4.84	−6.36
Erlotinib Hydrochloride	2	0.3	4.34	3.03	3.03
Ertapenem Sodium	3	38	−1.82	−0.72	−4.54
Erythromycin (Base)	3	5	1.61	2.83	1.69
Erythromycin Lactobionate	3	5	1.61	1.61	1.61
Erythromycin Stearate	4	5	1.61	1.61	1.61
Escitalopram	1	8	3.13	2.51	1.27
Esmolol	1	0.5	1.72	1.91	−0.08
Esomeprazole Magnesium	1	0.5	2.57	0.2	−2.57
Estazolam	2	4	2.29	3.25	2.5
Estradiol	1	0.5	3.78	4.13	3.62
Eszopiclone	1	5	1.25	−0.33	0.56
Ethambutol	3	79	0.12	−0.05	−2.13
Ethanol	1	2.5	−0.24	−0.19	−0.23
Ethchlorvynol	2	0.05	1.57	2.06	1.99
Ethinylestradiol	1	3	3.86	4.52	3.87
Ethosuximide	1	25	0.4	0.38	−1
Etidronic Acid	3	50	−2.54	−3.54	−9.4
Etizolam	2	0.3	2.868	2.63	2.87
Etodolac	2	1	3.43	3.59	0.44
Etomidate	2	2	2.67	3.26	2.55
Etonogestrel	1	0.1	5.68	3.32	3.32
Etoposide	3	38	0.03	0.3	0.66
Etoricoxib; Arcoxia	2	0.5	2.35	2.21	2.58
Etravirine	2	0	5.22	4.19	4.05
Everolimus	1	0	7.1	3.35	4.24
Exemestane	2	1	3.28	3.11	3.01
Exp-3174	3	55	5.59	4.79	−0.06
Ezetimibe	2	2	3.96	3.26	3.67
Famciclovir	1	0	0.09	−0.67	0.26
Famotidine	3	67	−1.17	−0.4	−1.43
Febuxostat	2	3	4.4	4.87	0.69
Felbamate	4	45	0.5	1.2	1.04
Felodipine	2	0.25	5.3	4.83	4.86
Fenofibrate	2	0.1	5.23	4.8	5.01
Fentanyl	1	8	3.62	3.89	3.01
Fesoterodine	1	0	4.36	5.07	2.28
Fexofenadine; Terfenadine Carboxylate	3	25	1.96	4.8	2.43
Finasteride	1	0.5	3.01	4.59	2.11
Flecainide	3	43	3.66	2.9	1.01
Fleroxacin	4	72.5	−0.33	1.72	−2.36
Fluconazole	3	75	−0.44	0.5	0.7
Flucytosine	3	99	−1.64	−1.11	−1.29
Fludarabine	1	24	−2.01	−0.4	−0.86
Fludrocortisone Acetate	1	1	1.54	2.32	2.24
Flufenamic Acid	2	7	5.53	5.62	2.29
Flumazenil	1	0.5	1.29	0.67	1
Flunarizine	2	0.2	6.34	4.74	4.68
Flunitrazepam	1	0.5	1.78	1.44	2.03
Fluorouracil	1	5	−0.58	−2.1	−4.15
Fluoxetine	1	1.25	4.57	4.09	1.75
Fluphenazine Hydrochloride	2	0.1	4.12	3.58	3.92
Flurazepam	1	0.1	4.22	3.99	1.2
Flurbiprofen	2	2.9	3.75	4.11	0.68
Flutamide	2	0.5	3.34	3.72	3.14
Fluticasone Propionate	2	3	3.8	3.73	3.71
Fluvastatin Sodium	1	1.5	4.05	5.76	4.69
Fluvoxamine	1	2	3.32	3.11	1.08
Formoterol Fumarate	1	8	1.26	4.43	4.43
Fosamprenavir Calcium	2	0	3.04	3.87	2.07
Foscarnet	3	82	−2.17	−2.53	−7.19
Fosfomycin Tromethamine	3	82	−0.23	1.79	−0.31
Fosinopril	2	0	7.45	6.09	1.9
Fosinoprilat	4	43	4.85	4.58	−1.28
Frovatriptan	1	6	0.72	0.85	−1.53
Fulvestrant	2	0.1	7.35	7.92	7.55
Furosemide	4	66	1.9	3.1	−0.78
Gabapentin	3	100	−0.66	1.19	−1.4
Galantamine	1	20	1.03	1.75	0.92
Gallium Nitrate	3	80	1.43	1.43	1.43
Ganciclovir Sodium	3	91	−2.73	−2.22	−4.72
Gefitinib	2	2	5.6	4.11	3.55
Gemcitabine Hydrochloride	1	8	−0.71	−2.89	−2.88
Gemfibrozil	2	0.5	3.94	4.39	1.58
Gentamicin C1 Sulfate	3	91	−1.8	−1.8	−1.8
Glibornuride	1	0.5	3.7	2.6	0.83
Gliclazide	2	0.5	1.09	1.57	0.16
Glimepiride	2	0	3.96	4.17	1.55
Glipizide	2	4.5	2.57	3.37	0.64
Glyburide (Glibenclamide)	2	0	4.24	5.19	2.25
Gold Sodium Thiomalate	3	70	−3.3	−3.4	−3.33
Goserelin	1	20	−2.86	−0.95	−4.35
Granisetron	1	11	1.72	1.47	−0.77
Griseofulvin	2	0.3	1.91	3.53	2.88
Guanfacine Hydrochloride	3	50	1.37	2.71	0.61
Haloperidol	2	1	3.85	3.01	2.65
Heparin; Enoxaparin	1	0.5	−9.69	−8	−8.86
Hexobarbital	1	0.5	1.63	1.59	1.84
Hydralazine Hydrochloride	1	8	0.66	2.11	1.82
Hydrochlorothiazide	3	100	−0.37	−0.07	−0.01
Hydrocodone	1	10.2	1.13	1.83	0.17
Hydrodolasetron	3	53	1.9	2.72	1.06
Hydroflumethiazide	3	90	−0.21	0.36	0.21
Hydromorphone	1	6	0.72	1.06	0.24
Hydroxychloroquine Sulfate	1	27	4.12	3.77	1.96
Hydroxyurea	3	80	−1.8	−1.22	−4.22
Hydroxyzine	1	0.1	4	2.03	2.66
Hyoscyamine; L-Atropine	3	57	1.3	1.4	1.1
Ibandronate	3	55	−3.37	−0.65	−6.09
Ibuprofen	2	0.5	3.68	3.72	0.45
Ibutilide	1	7	3.78	4.17	1.55
Idarubicin	1	3	0.9	2.95	0.38
Idebenone	2	0.5	3.42	3.49	3.41
Ifosfamide	1	10	0.92	0.23	0.68
Iloperidone	2	0.5	4.27	3.81	2.72
Iloprost	1	0	2.71	2.94	0.99
Imatinib Mesylate	2	5	4.53	2.89	2.49
Imidapril	1	5	1.53	0.55	−2.73
Imidaprilat	3	9	1.74	−0.34	−4.1
Imipenem	3	69	−1.35	−2.78	−3.66
Imipramine	1	1.5	5.04	4.8	2.68
Imiquimod	1	1	3.24	3.46	2.52
Inamrinone; Amrinone Lactate	1	25	−0.69	−0.54	−0.35
Indapamide	1	7	2.96	2.1	2.15
Indobufen	2	13	3.27	3.3	0.44
Indomethacin	2	15	4.18	3.11	0.75
Indoramin	2	5	2.84	2.85	2
Iohexol	3	95	0.66	−4.16	−3.17
Iopamidol	3	96	0.86	−2.09	−2.31
Iopanoic Acid; Iodopanoic Acid	4	33	4.7	4.19	1.23
Iopromide	3	97	1.37	−2.95	−2.12
Ipratropium Bromide	3	50	−2.19	3.11	3.11
Irbesartan	2	2.5	6.04	4.51	1.43
Irinotecan	1	16.7	2.73	4.35	2.14
Isoniazid	1	7	−0.67	−0.89	−0.63
Isosorbide 5-Mononitrate	1	2.5	−0.66	−0.51	−0.08
Isotretinoin; 13-Cis- Retinoic Acid	2	0.5	6.74	6.83	3.29
Isradipine	2	0	3.92	3.59	3.75
Itraconazole	2	0.03	5.99	4.35	4.96
Ivabradine	1	4	3.97	3.69	2.18
Ixabepilone	2	5.6	3.08	1.77	2.44
Kanamycin A	3	90	−5.17	−2.58	−7.93
Ketamine	1	4	2.93	2.18	2.07
Ketanserin	2	0.5	3	3.21	2.86
Ketoconazole	2	3	3.64	3.55	3.49
Ketoprofen	2	0.5	2.76	2.81	0.06
Ketorolac	3	58	1.62	2.08	−0.44
Labetalol	1	2.5	2.5	2.31	0.85
Lacosamide; Erlosamide	3	40	0.39	0.9	0.82
Lamivudine	3	67	−1.46	−0.71	−0.98
Lamotrigine	2	10	2.53	0.72	1.71
Lansoprazole	2	0	2.6	2.76	2.4
Lapatinib Ditosylate	2	1	5.97	6.3	6.26
Latamoxef; Moxalactam	3	76	−0.82	0.87	−4.93
Leflunomide	2	1	2.32	1.95	2.2
Lenalidomide	4	66	0.53	−1.39	−0.48
Letrozole	1	3.9	1.24	1.91	2.22
Leucovorin; Folinic Acid	3	10	−3.49	−3.19	−6.33
Leuprolide	1	2	−0.99	0.41	−2.77
Levalbuterol	3	46	0.06	0.01	−1.52
Levetiracetam	3	66	−0.34	−0.67	−0.74
Levobupivacaine	1	0.5	3.69	3.64	2.68
Levocabastine	4	70	1.86	4.29	1.97
Levocetirizine	3	71	2.08	2.16	−0.55
Levodopa	1	0.5	−2.82	−0.22	−2.7
Levofloxacin	3	74	−0.51	0.84	−2.08
Levonorgestrel	4	52	3.31	3.92	3.32
Lidocaine	1	8	1.95	3.63	1.26
Lincomycin	3	30	1.28	1.82	−0.86
Linezolid	1	30	0.17	0.3	0.82
Liraglutide	1	6	10	11	8.6
Lisinopril	3	94	−1.69	1.19	−1.8
Lithium Carbonate	3	95	−3.65	−3.65	−3.65
Lofepramine	2	4	7.29	6.96	6.21
Lomefloxacin	3	65	−0.11	1.71	−2.82
Loperamide	3	0.5	4.66	4.26	3.94
Lopinavir	2	2.2	6.1	6.26	5.24
Loracarbef	3	94	−0.47	−1.13	−4.14
Loratadine	2	5	5.05	5.94	5.32
Lorazepam	1	0.5	2.37	2.47	2.49
Lorcainide Hydrochloride	1	1	4.48	3.63	1.91
Losartan Potassium	2	12	4.1	3.3	3.3
Lovastatin	2	10	4.08	4.07	4.14
Maprotiline	1	3	4.52	4.51	2.1
Maraviroc	1	8	3.26	3.6	1.49
Mecamylamine	0	50	2.83	3.06	−0.04
Medroxyprogesterone Acetate	4	44	4.01	4.11	4.04
Mefenamic Acid	2	1	5.29	5.33	2.04
Mefloquine	2	9	3.67	2.87	1.47
Megestrol Acetate	4	60	3.58	3.82	3.83
Meloxicam	2	0.2	2.29	3.35	1.04
Melphalan	1	12	−0.21	1.79	−1.03
Memantine	3	71	3.03	3.18	0.56
Meperidine; Pethidine	1	13	2.23	2.35	1.88
Mepivacaine	1	5	2.1	2.04	1.4
Mercaptopurine; 6- Mercaptopurine	2	22	0.82	−0.18	−2.51
Meropenem	4	70	−3.28	−3.13	−4.09
Mesalamine; Mesalazine	2	7	1.06	0.46	−1.98
Metaxalone	2	2	2.15	2.42	2.29
Metformin	3	99	−1.63	−2.31	−3.36
Methadone	1	24	4.17	4.2	2.8
Methamphetamine	0	40	1.89	1.94	−0.57
Methaqualone	2	0.2	3.65	2.5	2.57
Methazolamide	3	61	0.09	0.13	−0.02
Methicillin	3	88	1.78	1.27	−2.23
Methohexital	1	0.5	1.81	2.36	2.06
Methotrexate	3	81	−0.53	−0.24	−5.22
Methyldopa	3	40	−2.26	−0.09	−2.39
Methylnaltrexone	3	52.75	−2.64	−3.57	−2.61
Methylprednisolone	1	4.9	1.74	1.99	1.97
Metoclopramide	3	20	2.23	3.1	−0.36
Metocurine Iodide	3	50	1.12	1.31	1.25
Metoprolol	1	10	1.49	1.79	−0.25
Metronidazole	1	10	−0.46	−0.01	0.05
Mexiletine	1	9.5	2.57	2.16	1.23
Mezlocillin	3	45	1.5	−1.18	−3.94
Mianserin	1	5	3.76	3.67	3.23
Micafungin Sodium	1	1	−2.59	−2.6	−2.7
Miconazole	2	0	5.81	5.93	6.13
Midazolam Hydrochloride	1	5.6	3.42	3.8	3.78
Miglitol	3	80	−1.26	−1.4	−2.07
Miglustat	3	85	0.91	0.46	−0.84
Milnacipran	3	55	1.91	1.23	−1.09
Milrinone	3	85	−0.03	1.43	−1.3
Minocycline Hydrochloride	1	11	0.19	1.93	−2.55
Minoxidil	1	10	−0.72	0.34	0.16
Mirtazapine	1	2	2.81	2.75	2.4
Misoprostol	1	0.5	3.07	2.91	3.28
Mitoxantrone	3	7	2.3	0.45	−1.19
Mizolastine	2	5	2.839	3.42	2.59
Modafinil	2	8	0.94	1.17	1.37
Molindone	1	2	2.57	1.96	2.14
Mometasone Furoate	2	0.5	4.12	4.27	3.96
Montelukast Sodium	2	0.2	8.47	5.74	5.24
Morphine 6-Glucuronide	3	90	−3.1	−1.6	−3.82
Morphine hydrochloride	1	4	0.57	1.33	−0.25
Moxifloxacin Hydrochloride	3	22	−0.08	2.83	0.31
Mycophenolate	2	0.5	2.29	5.69	5.69
Mycophenolate Mofetil	2	0	2.98	3.15	3.59
Nabumetone	2	0	2.98	2.82	2.92
Nadolol	3	73	0.38	1.29	−0.86
Nafarelin	1	3	−1.22	−1.22	−1.22
Nafcillin Sodium	3	27	3.53	8.16	8.24
Nalbuphine Hydrochloride	1	4	1.39	1.22	0.81
Nalmefene Hydrochloride	1	9.6	2.64	2.82	1.95
Naloxone	1	0	0.16	1.45	1.42
Naltrexone	1	1	0.36	1.8	1.18
Naproxen	2	0.5	2.82	3	0.45
Naratriptan	3	50	1.7	1.35	−0.22
Nateglinide	2	13	4.3	4.21	0.63
Nefazodone	2	0.1	5.73	3.5	3.88
Nefopam	1	3	2.91	3.44	1.75
Nelarabine	2	6.6	−0.46	−0.58	−0.98
Neomycin B Sulfate	3	40	−6.47	−6.47	−6.47
Neostigmine	3	67	−2.81	−3.03	−2.77
Netilmicin	3	85	−2.4	−1.9	−7.26
Nicardipine	1	0	5.23	5.13	4.55
Nicorandil	1	0.5	0.75	0.72	0.93
Nicotine	1	16.7	0.88	0.72	−0.37
Nifedipine	2	0.01	3.13	2.97	3.45
Nifurtimox	2	1	0.02	0.73	0.73
Nilotinib	2	4	5.84	5.15	4.74
Nilvadipine	2	0	3.04	1.72	3.23
Nimesulide	2	2	3.21	3.79	1.33
Nimodipine	2	0.5	4	3.86	4.13
Nitrazepam	2	0.5	2.32	1.09	1.02
Nitrendipine	2	0.5	3.73	3.5	3.76
Nitrofurantoin	4	47	−0.47	−0.4	−0.26
Nitroglycerin	1	0.5	1.76	2.32	2.41
Nizatidine	3	61	−0.16	1.18	−0.05
Norethindrone	1	2	2.78	3.38	2.98
Norethindrone Acetate	2	0	3.93	3.99	3.72
Norfloxacin	4	29	−0.78	0.82	−3
Norgestimate	1	0	5.06	5	4.84
Norgestrel	1	0	3.31	3.92	3.32
Nortilidine	1	3	3.16	2.83	0.97
Nortriptyline	1	2	4.32	5.65	2.28
Octreotide Acetate	1	32	2.51	2.51	2.51
Ofloxacin	3	64	−0.51	0.84	−2.08
Olanzapine	2	7	3.01	2.18	1.9
Olmesartan	3	43	2.51	3.72	−0.39
Olmesartan Medoxomil	1	0	2.91	5.23	2.15
Olopatadine Hydrochloride	3	65	1.09	0.23	−2
Omeprazole	1	0	2.57	2.17	2.08
Ondansetron	1	5	2.72	2.07	2.43
Orlistat	4	1	8.61	8.94	8.95
Orphenadrine	1	8	3.9	4.12	2.72
Oseltamivir	3	99	−1.24	2.52	0.54
Oseltamivir Phosphate	1	2	2.13	1.71	0.9
Oxacillin	3	46	2.05	2.53	−1.21
Oxaprozin	2	0.5	2.95	4.19	0.84
Oxatomide	2	0	5.62	3.57	3.79
Oxazepam	2	0.5	2.31	2.31	2.06
Oxprenolol	1	3	2.09	2.29	0.19
Oxybutynin Hydrochloride	1	0.5	4.87	5.05	4.15
Oxycodone	1	19	−0.04	1.67	0.45
Oxymorphone	1	1.9	−0.48	0.9	0.6
Paclitaxel	2	5	4.73	7.38	3.89
Paliperidone	4	59	1.12	1.52	0.88
Palonosetron Hydrochloride	3	40	2.18	4.58	4.58
Pamidronate Disodium	3	46	−6.17	5.39	0.98
P-Aminosalicylic Acid (PAS)	1	2	1.06	1.14	−1.68
Pancuronium Bromide	3	67	1.21	−0.77	−0.77
Pantoprazole Sodium	1	0	2.11	3.93	3.93
Paricalcitol	2	0	5.69	5.83	5.35
Paroxetine	1	2	4.24	3.89	1.46
Pefloxacin	1	12	−0.32	1.51	−2.17
Pemetrexed Disodium	3	80	−1.17	6.8	3.9
Penciclovir	3	75	−2.72	−3.58	−4.7
Penicillamine	3	45	−1.73	0.93	−1.84
Pentamidine	1	12	2.31	2.47	−0.9
Pentazocine	2	15	4.67	4.53	2.26
Pentostatin	3	80	−1.96	−2.4	−2.09
Pentoxifylline	1	0	0.12	0.32	0.54
Perindopril Erbumine	1	8	1.21	3.2	3.19
Phenazopyridine Hydrochloride	4	41	2.05	2.21	2.21
Phenmetrazine	0	19	1.67	1.53	0.46
Phenobarbital	1	24	1.37	1.14	−3.48
Phenylbutazone	1	1	3.39	3.16	0.59
Phenylethylmalonamide	3	79	0.01	0.13	0.21
Phenylpropanolamine	3	65	0.58	0.81	−1.15
Phenytoin Sodium	2	2	2.09	1.74	−0.71
Pimecrolimus	2	0	5.3	5.08	5.07
Pindolol	3	54	1.67	1.97	−0.32
Pioglitazone	2	0.5	3.53	2.94	1.53
Pipecuronium Bromide	3	39	0.63	2.83	2.83
Piperacillin	3	71	1.7	0.62	−4.49
Piperazine	3	50	−1.48	−1.17	−3.05
Piracetam	3	70	−1.18	−1.39	−3.41
Pirenzepine	3	43	−0.35	−0.08	0.03
Piroxicam	2	5	1.89	2.23	0.46
Plerixafor	3	70	−0.25	0.2	−5.39
Posaconazole	2	0.1	4.11	2.25	3.7
Potassium Chloride	3	85	−2.14	−3	−2.34
Pramipexole	3	90	1.17	1.42	−0.3
Prasugrel	2	1	3.43	4.31	2.39
Pravastatin	3	20	2.05	1.35	−0.75
Prazepam	2	0	3.93	3.81	3.53
Praziquantel	2	2	3.36	2.44	2.71
Prazosin	1	0.5	2.03	−0.26	0.51
Prednisolone	1	16	1.42	1.5	1.66
Prednisone	2	3	1.66	1.57	1.64
Pregabalin	3	90	−0.92	1.12	−1.75
Primaquine	1	1	2.6	2.67	−0.56
Primidone	2	35	0.88	0.03	−0.66
Probenecid	2	1.2	3.37	3.3	0.01
Procainamide	3	67	1.42	1.1	−0.65
Prochlorperazine	1	0.1	4.38	4.61	4.22
Progesterone	2	0	3.78	4.04	3.72
Promazine	1	2	4.4	4.63	2.69
Promethazine	1	2	4.4	4.78	3.1
Propafenone Hydrochloride	2	0.5	3.64	3.35	1.37
Propantheline Bromide	1	3.5	1.49	−2.45	−2.44
Propofol	2	0.5	3.93	4.16	3.88
Propranolol Hydrochloride	1	0.25	2.75	2.39	−0.24
Protriptyline	1	1	4.87	5.06	1.85
Pseudoephedrine	3	43	0.89	1.05	−0.75
Pyrantel Pamoate	2	7	3.03	3.13	3.12
Pyrazinamide	1	1.6	−0.68	−0.83	−2.71
Pyridostigmine	3	85	−4.26	−4.31	−3.34
Pyrimethamine	3	65	3	1.03	0.19
Quetiapine Fumarate	1	0.5	2.99	2.6	2.51
Quinapril	2	3.1	1.74	4.32	−0.11
Quinaprilat	3	96	1.95	3.44	−1.57
Quinidine Sulfate Dihydrate	1	18	2.79	2.7	2.7
Quinine Bisulfate Heptahydrate	1	12	2.79	2.7	2.7
Quinupristin	4	3.5	7.05	0.77	−1.3
Rabeprazole Sodium	1	0	2.08	2.1	2.09
Raloxifene; Keoxifene	2	0.1	6.86	6.8	4.4
Raltegravir Potassium	2	9	1.16	−0.61	−4.66
Raltitrexed	3	50	0.71	−1.28	−5.15
Ramelteon	1	0.1	2.49	2.57	3.07
Ramipril	1	1.5	1.54	3.41	−0.13
Ramiprilat	3	13	1.75	2.53	−1.58
Ranitidine	3	30	0.67	1.23	−0.63
Ranolazine	2	6	1.01	3.47	2.44
Reboxetine	1	10	3.26	2.82	2.05
Regadenoson	3	65	−2.86	−3.09	−1.82
Remifentanil Hydrochloride	1	0.1	1.96	1.79	1.75
Repaglinide	2	1.5	5.3	4.69	2
Reserpine	1	1	3.86	4.05	3.93
Ribavirin	1	17	−2.85	−2.26	−2.07
Rifabutin	2	10	4.73	3.45	1.62
Rifampin	2	7	3.71	1.09	−0.28
Rifaximin	4	0.035	7.24	3.22	0.72
Riluzole	1	2	3.24	2.84	2.44
Rimantadine Hydrochloride	1	20	3.96	7.19	7.19
Risedronate	3	87	−2.62	−2.94	−8.84
Risperidone	1	3	2.71	2.88	1.81
Ritodrine	3	10	1.65	1.61	−0.06
Ritonavir	2	3.5	4.94	6.75	2.68
Rivastigmine	1	0.1	2.1	2.14	1.09
Rizatriptan	1	14	0.99	0.96	0.04
Rocuronium Bromide	3	17	6.4	0.2	−1.33
Rofecoxib	2	1	1.8	1.34	2.07
Rolitetracycline	3	55	0.47	−0.13	−3.14
Ropinirole	1	5	2.8	3.19	1.21
Ropivacaine	1	1	3.16	3.11	2.32
Rosiglitazone Maleate	1	0	3.02	2.61	2.07
Rosuvastatin Calcium	3	5	1.9	1.9	1.9
Rotigotine	1	0	4.54	4.96	3.28
Roxatidine	3	57.5	2.35	1.57	0.19
Roxatidine Acetate Hcl	1	2	2.8	2	0.43
Roxithromycin	4	12	2.29	3.73	2.8
Rufinamide	2	1	0.51	0.05	0.42
Salicylic Acid	1	15	2.19	2.06	−0.77
Salmeterol Xinafoate	2	2.5	3.06	3.71	1.79
Saquinavir Methanesulfonate	2	2	4.73	5.08	5.11
Saxagliptin	3	24	0.11	−0.14	−0.2
Scopolamine	1	6	0.29	0.76	0.3
Selegiline; (−)-Deprenil	1	0.1	3.02	2.95	2.51
Sertraline Hydrochloride	1	0.2	5.35	3.26	1.61
Sibutramine	1	0	5.59	5.43	2.9
Sildenafil	1	7.5	1.98	2.27	1.79
Simvastatin	2	10	4.48	4.41	4.6
Sirolimus	2	2	7.04	3.54	4.21
Sitafloxacin	3	75	−1.25	0.87	−0.87
Sitagliptin	3	78	0.69	1.3	1.09
Sn-38	2	0.5	1.97	2.31	2.09
Solifenacin Succinate	1	12.5	4.68	2.71	1.85
Sorafenib Tosylate	2	0	5.46	0.74	−1.37
Sotalol	3	85	0.23	0.32	−1.63
Sparfloxacin	1	10	−0.61	1.2	−1.7
Spectinomycin	3	70	−2.88	1.27	−1.31
Spironolactone	2	0.5	2.65	3.12	2.78
Stavudine	3	39	−0.49	−1.25	−3.82
Streptomycin	3	55	−4.26	−2.53	−7.19
Sufentanil	1	6	3.59	3.38	3.38
Sulfadiazine	4	57	0.1	−0.12	−0.79
Sulfamethizole	4	86	0.42	0.51	−1.14
Sulfamethoxazole	2	14	0.56	0.89	−0.56
Sulfasalazine	2	1.5	3.88	3.18	0.22
Sulfinpyrazone	2	39	1.66	2.3	−0.22
Sulfisoxazole	4	49	0.22	1.01	−0.77
Sulindac	2	1	3.16	3.59	0.33
Sulindac Sulfide	2	0.5	3.16	5.74	2.21
Sulpiride	3	70	1.11	0.45	−0.99
Sumatriptan Succinate	1	22	0.74	0.44	−1.45
Sunitinib Malate	1	4	3	4.21	2.21
Tacrine	1	0.5	3.27	1.78	0.89
Tacrolimus	2	0.5	5.78	3.96	4.09
Talinolol	3	52.8	3.15	3.2	0.7
Tamoxifen	1	0.5	6.82	7.88	5.51
Tamsulosin	1	8.7	2.17	2.24	0.77
Tazobactam Sodium	3	77	−0.65	0.6	−3.13
Tegaserod Maleate	2	0.5	2.81	3.22	2.72
Telithromycin	2	13	3.75	4.52	3.62
Telmisartan	2	0.5	7.54	7.73	4.01
Temazepam	1	0.5	2.34	2.15	2.11
Temocapril	1	1.5	2.1	4.39	−0.04
Temocaprilat	3	29.5	2.556	3.51	−2
Temozolomide	2	5.6	−0.81	−1.32	−0.99
Temsirolimus	1	4.6	0.67	2.96	4.12
Teniposide	2	9	0.72	1.71	1.42
Tenofovir Disoproxil	3	82	0.8	2.04	1.51
Tenoxicam	1	0.1	1.61	1.52	−1.12
Terazosin	1	10	2.18	−0.96	0.5
Terbutaline	3	56	0.48	0.48	−1.61
Terfenadine	2	0	6.07	6.51	3.66
Tetrabenazine	2	0	3.81	3.48	3.12
Tetracycline	3	58	−0.91	−1.47	−3.55
Tetracycline Hydrochloride	3	58	−0.91	−0.91	−0.91
Thalidomide	2	0.5	0.53	0.54	0.48
Theophylline	1	18	−0.03	−0.17	−0.03
Thiabendazole	2	0.1	2.36	2.47	2.39
Thioguanine	1	0.5	−1.7	−0.99	−3.59
Thiopental	1	0.5	2.98	2.99	2.48
Thyroxine; Levothyroxine	2	0	3.51	5.93	1.76
Tiagabine Hydrochloride	2	2	2.78	4.09	4.09
Tiaprofenic Acid	2	2.5	2.54	2.42	−0.2
Tibolone	2	0	3.15	4.03	4
Ticarcillin	3	77	1.28	0.69	−3.7
Ticlopidine	1	0.5	4.39	3.77	3.93
Tigecycline	3	22	−0.83	−1.3	−2.73
Tilidine; Tilidate	1	0.1	3.76	3	2.03
Tiludronic Acid	3	60	0.26	−0.32	−6.87
Timolol	1	15	1.21	0.68	−0.35
Tinidazole	1	22.5	−0.32	−0.27	−0.38
Tiotropium Bromide	3	74	−1.71	2.55	−3.57
Tipranavir	2	0.1	7.76	7.2	2.73
Tirofiban Hydrochloride	3	65	2	1.67	0.94
Tobramycin	3	93	−4.72	−3.41	−9.45
Tocainide	3	38	0.26	0.76	0.17
Tolbutamide	2	0	2.5	2.93	0.47
Tolcapone	2	0.5	3.25	4.07	1.22
Tolfenamic Acid	2	8	5.66	5.76	2.47
Tolmetin	2	7	2.21	1.55	−0.68
Tolterodine	1	1	5.24	5.77	2.57
Tolvaptan	2	0	4.65	4.09	4.21
Topiramate	3	70	0.04	2.97	2.14
Topotecan	3	40	0.73	1.08	0.68
Toremifene	1	0.1	6.53	7.82	5.56
Torsemide; torasemide	2	20	3.36	3.53	1.44
Tramadol	1	20	3.1	2.51	0.52
Trazodone	2	0.5	3.85	1.66	2.59
Treprostinil	2	4	3.72	3.5	−0.12
Tretinoin	2	0.5	6.74	6.83	3.26
Triamcinolone	1	1	0.71	0.83	0.92
Triamcinolone Acetonide	1	1	2.21	2.5	2.57
Triamterene	2	10	1.61	−1.72	−1.61
Triazolam	1	2	2.62	2.66	3.01
Triclabendazole	2	2	6.44	5.97	5.63
Triclabendazole Sulfoxide	4	6.5	4.36	4.12	3.56
Trimetazidine	3	62	1.18	0.8	−0.43
Trimethoprim	3	70	0.98	0.38	−1.15
Trimetrexate Glucuronate	1	20	1.84	2	1.2
Triptorelin	3	41.7	−1.22	−0.41	−3.47
Tropisetron	1	8	2.88	3.55	0.71
Trospium Chloride	3	6	−1.16	0.7	0.07
Tubocurarine	3	63	3.55	0.08	−0.13
Urapidil	1	15	2.44	2.28	0.98
Ursodiol; Ursodeoxycholic Acid	2	0.5	4.51	4.66	1.14
Valacyclovir	1	0.5	−1.22	−0.88	−1.49
Valproic Acid	1	1.8	2.76	2.72	0.1
Valsartan	4	13	4.86	4.75	−0.87
Vancomycin	3	79	−1.14	−1.44	−5.14
Vardenafil	1	4	2.23	2.65	1.83
Varenicline Tartrate	3	92	0.9	1	−1.06
Vasopressin	1	5	−3.82	−5.74	−8.64
Vecuronium Bromide	3	20	4.33	5.2	2.53
Venlafaxine Hydrochloride	1	4.6	3.27	2.48	0.76
Verapamil Hydrochloride	1	1.5	4.47	3.83	2.27
Vigabatrin	3	60	−2.22	−0.1	−2.73
Vinblastine	1	0.5	5.23	4.18	3.68
Vincristine	1	15	4.04	2.82	2.6
Vinorelbine Tartrate	1	11	5.94	4.68	4.64
Vitamin A (Retinol)	2	0	6.4	6.84	6.01
Vitamin B1 (Thiamine)	3	90	−5.97	−4	−4.5
Vitamin B2 (Riboflavin)	4	75	−0.73	−2.01	−4.88
Vitamin C; Ascorbic Acid	0	25	−1.76	−2.41	−4.99
Voriconazole	2	1.5	0.52	0.93	1.39
Vorozole	1	8	2.2	1.15	1.15
Warfarin	2	1	2.9	3.42	0.3
Zafirlukast	2	0	7.09	6.15	3.78
Zalcitabine	3	65	−1.25	−2.07	−3.9
Zaleplon	2	0.5	1.44	0.87	1.45
Zanamivir	3	100	−5.56	−4.13	−6.03
Zidovudine	1	2.8	0.04	−0.53	−0.09
Ziprasidone Hydrochloride	2	0.5	4.21	2.97	2.29
Zoledronic Acid	3	39	−3.07	−2.28	−8.39
Zolmitriptan	1	8	1.29	1.64	0.44
Zolpidem Tartrate	1	0.5	3.03	4.66	4.66
Zonisamide	1	22	−0.36	−0.1	0.45
Zopiclone	1	4.5	1.25	−0.33	0.56

Determination of a threshold value

%A_e data for compounds in BDDCS classes 0, 1 and 2 (observed low UE values), and those in BDDCS classes 3 and 4 (observed high UE values) were combined as:

1. LUE (low UE, N=541)

2. HUE (high UE, N=293)

A threshold value (TV) of %A_e, which would distinguish between the compounds in LUE and HUE groups was determined using the ROC curve toolbox in SigmaPlot 11.0 (Systat Software, San Jose, CA). A paired sensitivity and specificity values were computed for each potential TV where sensitivity is the ratio of positives selected by the test for the true positives and specificity is the ratio of negatives selected by the test for the true negatives [15]. In a ROC curve, sensitivity values are plotted against the respective 1–specificity values [16]. A TV with sensitivity, specificity, and AUC (area under the ROC curve) values greater than 0.8 is considered to be statistically significant [11, 12, 17]. Therefore, the probability for distinguishing true positives from true negatives is ≥80%.

Positives according to the test refer to the compounds having a value greater than a certain TV for the test parameter, whereas negatives refer to compounds having a parameter value less than the TV. For the purpose of the present study, fraction of correctly classified compounds in the LUE group represented the true positive fraction and fraction of correctly classified compounds in the HUE group represented the true negative fraction.

Evaluation of physicochemical indicators of extent of UE

All compounds were divided into two new groups according to the TV obtained from the ROC curve analysis for a priori determination of high/ low UE classes as:

1. Compounds with %A_e ≤ROC TV (ROC-LUE)

2. Compounds with %A_e >ROC TV (ROC-HUE)

All 18 physicochemical properties were evaluated to determine a TV that could be used to distinguish between compounds in ROC-LUE and ROC-HUE groups using the ROC curve analysis for a priori determination of the extent of UE. In the absence of a TV, statistically significantly different medians could potentially be used as two unique cut-off values for a priori determination of high/ low UE classes of NMEs. Therefore, the Mann–Whitney rank test for medians was performed to compare medians of these 18 physicochemical properties of ROC-LUE and ROC-HUE groups, using SigmaPlot 11.0 (Systat Software, San Jose, CA).

Linear regression for predicting percent of dose excreted unchanged into urine (%A_e)

Simple linear regression and stepwise multiple linear regression methods were implemented to determine quantitative structure pharmacokinetics relationships (QSPKR) between %A_e of compounds and 18 physicochemical parameters using Minitab^® 16 Statistical Software (Minitab Inc., State College, PA). Regression models were evaluated for (1) all 834 compounds, (2) compounds in ROC-HUE and ROC-LUE groups, and (3) compounds with unique ion status – anions, cations, zwitterions, and neutral compounds. A regression model with R²_adj > 0.5 would be considered to have strong predictive power [18].

Evaluation of physicochemical space

The physicochemical space of compounds in ROC-LUE and ROC-HUE groups was evaluated using a multivariate statistical method known as the principal component analysis (PCA) using PCA multivariate method in Minitab^® 16 Statistical Software (Minitab Inc., State College, PA). In brief, PCA was performed using 18 physicochemical descriptors (as listed above) and the scores of the first two resulting components, which account for >90% correlation and covariance of these descriptors, were calculated and plotted as a XY scatter plot. Each XY pair would then represent the physicochemical space of a respective compound [18].

External validation

Data on the percent of dose excreted unchanged into urine (%A_e) and associated physicochemical properties of 90 FDA approved NMEs (2011–2016) was collected from FDA approved product labels and ChemSpider and ChEMBL databases [13, 14], respectively, for the external validation of our approach (Table 3). Percentage of correctly classified compounds was also computed as the quantitative metric for the goodness-of-prediction.

Table 3.

List of %A_e, cLogP, ACD labs cLogP, and ACD labs cLogD (pH=7.4) of 90 compounds in the external validation set.

Compounds	%Ae	cLogP	ACD cLogP	ACD cLogD (pH=7.4)
Aclidinium Bromide	0.09	3.87	1.78	1.49
Afatinib	4	3.36	3.59	2.87
Alectinib	0.5	5.59	5.48	4.83
Alogliptin	76	1.84	1.84	1.35
Apixaban	0	1.83	3.87	3.87
Apremilast	3	1.39	1.75	1.74
Avanafil	<1	2.42	1.83	1.84
Axitinib	0	3.77	2.39	2.39
Bedaquiline	0	7.59	7.59	5.32
Belinostat	2	1.84	2.24	2.16
Boceprevir	3	1.78	2.05	2.4
Bosutinib	3	4.88	5.27	1.72
Brexpiprazole	<1	4.65	5.8	5.8
Cabozantinib	27	NA	−3.38	−3.38
Canagliflozin	<1	3.52	5.54	3.75
Cariprazine	1.2	4.06	5.8	4.6
Ceritinib	1.3	5.81	2.92	5.03
Clobazam	2	1.94	1.69	2.23
Cobimetinib	1.6	5.04	5.98	2.68
Crizotinib	2.3	4.88	4.73	1.9
Dabrafenib	0	5.48	3.54	2.94
Daclatasvir	6.6	3.47	5.54	4.47
Dalbavancin	33	−0.61	−1	−1.68
Dapaglifozin	2	1.8	4.42	2.48
Deferiprone	80	−0.35	−0.22	−0.45
Dolutegravir	<1	1.01	−1.32	−3.1
Droxidopa	75	−2.7	−0.95	−3.58
Eliglustat	<1	1.46	3.61	2.13
Eluxadoline	<1	5.98	4.35	2.87
Empagliflozin	27	1.66	3.38	2.46
Enzalutamide	<1	4.16	2.98	2.98
Ezogabine	36	2.7	0.81	2.24
Fidaxomicin	0.56	8.56	10.7	6.5
Gadobutrol	90	−9.4	NA	NA
Ibrutinib	0	3.63	2.86	2.92
Icatibant	10	−7	−8	−8
Idelalisib	7	3.36	1.83	0.69
Ingenol Mebutate	0	2.49	4.15	1.01
Ivabradine	4	2.72	5.64	3.42
Ivacaftor	0	5	5.42	5.42
Ixazomib	3.5	4.27	2.82	2.33
Lesinurad	30	4	5.93	0.91
Linagliptin	4	2.18	4.92	4.92
Lomitapide	0	7.78	7.78	5.96
Lorcaserin Hydrochlorid	<1	3	3.72	3.61
Luliconozole	<1	3.61	3.98	4.51
Macitentan	0	3.69	5.41	2.13
Miltefosine	<0.2	2.25	3.41	4
Mirabegron	25	2.2	0.55	−1.79
Nintedanib	1.4	2.78	2.59	2.49
Olaparib	<1	2.32	1.04	1.04
Omacetaxine Mepesuccinate	15	1.88	2.09	2.06
Oritavancin	5	1.5	4.1	1
Osimertinib	2	4.49	3.3	8.86
Ospemifene	0.2	5.56	6.98	6.01
Palbociclib	6.9	4.12	2.14	1.06
Panobinostat	2.5	2.39	2.1	1.17
Pasereotide	7.6	3.03	NA	NA
Peramivir	90	−2.2	−1.37	−3.41
Perampanel	<1	2.26	1.36	1.36
Pirfenidone	<1	2.14	1.82	2.69
Pomalidomide	8	−0.16	−0.74	−0.09
Ponatinib	5	3.94	3.79	3.4
Regorafenib	2	4.38	4.2	4.2
Rilpivirine	1	5.47	3.63	3.63
Riociguat	<1	2.69	2.02	1.65
Rivaroxaban	1	1.9	1.84	1.83
Roflumilast	0	4.45	2.3	2.3
Rolapitant	8.3	5	4	4.27
Rxolitinib	1	2.1	5.81	5.81
Selexipag	12	3.76	4.3	2.31
Simeprevir	1	4.56	4.9	2.55
Sofosbuvir	3.5	1.92	2.21	2.21
Sonidegib	0	7.2	5.43	5.17
Sugammadex	95	−5.42	−1.25	−13.8
Suvorexant	23	3.5	3.32	3.65
Tafluprost	0	4.46	3.83	3.83
Tasimelteon	1	2.2	1.75	2.18
Tedizolid Phosphate	<3	0.97	0.69	−3.88
Telaprevir	1	2.58	3.93	3.2
Teriflunomide	<1	2.09	1.52	−0.91
Ticagrelor	1	1.9	1.9	2.3
Tofacitinib	30	1.8	3.83	3.83
Trabectedin	0	3.99	3.1	3.03
Trametinib	<0.1	3.18	2.68	2.34
Vandetanib	25	4.54	5.51	3.26
Vilazodone Hydrochloride	1	3.72	4.64	4.64
Vismodegib	4.4	4.22	2.98	3.13
Vorapaxar	0	5.1	4.54	4.75
Vortioxetine	0	3.48	4.26	3.37

RESULTS

Determination of the threshold value

Compounds in group LUE have significantly lower values of %A_e than those in HUE group as illustrated in figure 1A. The quantitative threshold of %A_e=16.8% with sensitivity=0.93, specificity=0.92, and AUC=0.97 was obtained from the ROC curve as illustrated in figure 1B. Consistent with sensitivity and specificity of the TV of 16.8%, 92% of compounds in group LUE have A_e≤16.8% and 92% of compounds in HUE have A_e>16.8%. Using the TV of 16.8%, compounds in group ROC-LUE (N = 523) could be clearly distinguished from those in ROC-HUE group (N = 311) as illustrated in figure 1C.

Figure 1.

(A) Boxplot of %A_e of compounds in groups LUE (N = 541) and HUE (N = 293), (B) Receiver operating characteristic (ROC) curve (Sensitivity vs. 1 – Specificity) of potential threshold values of %A_e [AUC = 0.97, sensitivity = 0.92, specificity = 0.93, P–value < 0.0001] for groups, LUE and HUE and (C) Boxplot of %A_e of compounds in groups ROC-LUE (N = 523) and ROC-HUE (N = 311); the box itself (from top-to-bottom) represents 75th-, median, 25th-percentiles, the whiskers are 10th and 90th percentiles, and closed circles are outliers.

Evaluation of physicochemical indicators of extent of UE

Of the 18 physicochemical properties evaluated, statistically significantly different medians were obtained for cLogP, ACD labs cLogP, ACD labs cLogD_(pH=7.4), PSA, MLogP, and MLogD (pH=7.4) for groups ROC-LUE and ROC-HUE, as described in table 2. We have focused on the analyses of cLogP, ACD labs CLogP, and ACD labs cLogD_(pH=7.4) as the indicators of the extent of UE because (1) MLogP and MLogD data were only available for 390 and 433 compounds, respectively, and (2) cut-off values of PSA could only correctly classify <50% of compounds in ROC-LUE and ROC-HUE groups.

Table 2.

Comparison of medians of the physicochemical determinants of the extent of urinary excretion for compounds in groups, ROC-LUE and ROC-HUE using Mann-Whitney rank test for medians; IQB – Interquartile boundary.

	ROC-LUE				ROC-HUE
Name	N	Median	25 % IQB	75 % IQB	N	Median	25 % IQB	75 % IQB	p- value
cLogP	523	3.0	1.7	4.3	311	0.3	− 1.3	1.6	<0.001
MLogP	248	2.8	1.7	3.8	142	0.6	− 0.6	1.7	<0.001
MLogD(pH=7.4)	276	1.7	0.5	2.7	157	− 0.7	− 1.7	0.4	<0.001
PSA (A2)	523	67	41	104	311	103	66	151	<0.001
cLogP(ACD labs)	523	2.9	1.6	4.1	311	0.7	−0.7	1.9	<0.001
cLogD(ACD labs, pH 7.4)	523	3.0	1.7	4.2	311	−1.1	−3.3	0.2	<0.001

In the ROC-LUE group, 90% of compounds (N=291) with cLogP ≥3.0 had A_e ≤16.8% and in the ROC-HUE group, 78% of compounds (N=195) with cLogP ≤0.3 had A_e >16.8%. However, we could not account for compounds with cLogP values between 0.3 and 3 (41% of compounds). We found similar results for ACD labs cLogP and ACD labs cLogD_(pH=7.4) as well, where we were able to classify >80% compounds correctly using the two medians as the cut-off values; however, we could not account for ~50% of compounds in the dataset. We, therefore, evaluated other values of (1) cLogP between 3.0 and 0.3, (2) ACD Labs cLogP between 2.9 and 0.7, and (3) ACD labs cLogD_(pH=7.4) between 3.0 and −1.1 with increments of 0.025 for the two groups, and observed that optimal cut-off values (in terms of % correctly classified compounds and % of dataset that is accounted for) were:

1. cLogP: ≤0.7 for ROC-HUE and ≥1.0 for ROC-LUE; In group ROC-LUE, 81% of compounds with cLogP ≥1.0 had A_e ≤16.8% and in group ROC-HUE, 73% of compounds with cLogP≤0.7 had A_e ≥16.8%

2. ACD labs cLogP: ≤0.7 for ROC-HUE and ≥1.0 for ROC-LUE; In group ROC-LUE, 76% of compounds with cLogP ≥1.0 had A_e ≤16.8% and in group ROC-HUE, 71% of compounds with cLogP≤0.7 had A_e ≥16.8%

3. ACD labs cLogD_(pH=7.4): ≤0.0 for ROC-HUE and ≥0.5 for ROC-LUE; In group ROC-LUE, 72% of compounds with cLogD ≥0.5 had A_e ≤16.8% and in group ROC-HUE, 70% of compounds with cLogD≤0.0 had A_e ≥16.8%

Although, we still could not account for the compounds (~4%) with values between the two cut-off values for each of the three parameters, we were able to incorporate 96% of the dataset and correctly classify >70% of compounds in both groups. This also indicated that any one of the three parameters can be used to determine of the extent of UE of NMEs independently as the three performed equally. In other words, determination of UE class using cLogP and cLogD was found to be comparable in our analysis. Since, cLogD accounts for the ion status of compounds, we recommend using both cLogP (ChemAxon or ACD labs) and cLogD (pH=7.4, ACD labs) to determine the extent of UE of compounds.

Linear regression for predicting percent of dose excreted unchanged into urine (%Ae)

We observed that %A_e of 834 compounds was strongly correlated with respective cLogP with r = −0.56. Results from simple linear regression of all 834 compounds indicated that cLogP was the single most important determinant of %A_e compared to other physicochemical parameters.

$$\%{\mathrm{A}}_{\mathrm{e}}=-6.4\times \mathrm{c}\text{Log}\mathrm{P}+36\hspace{1em}({{\mathrm{R}}^2}_{\text{adj.}}=0.33)$$ Eq. 1

As indicated in the equation above, cLogP, however, was not a statistically significant quantitative predictor of %A_e (since R²_adj. <0.5). In other words, although compounds with high values of cLogP undergo low UE and vice-versa, cLogP values of compounds cannot be used to predict the value of %A_e of compounds. Similar results were obtained with ACD labs cLogP and ACD labs cLogD_(pH=7.4):

$$\%{\mathrm{A}}_{\mathrm{e}}=-5.7\times \mathrm{A}\mathrm{C}\mathrm{D}\text{ labs }\mathrm{c}\text{Log}\mathrm{P}+36\hspace{1em}({{\mathrm{R}}^2}_{\text{adj.}}=0.30)$$ Eq. 2

$$\%{\mathrm{A}}_{\mathrm{e}}=-4.9\times \mathrm{A}\mathrm{C}\mathrm{D}\text{ labs }\mathrm{c}\text{Log}\mathrm{D}(\mathrm{p}\mathrm{H}=7.4)+27\hspace{1em}({{\mathrm{R}}^2}_{\text{adj.}}=0.31)$$ Eq. 3

The observed vs. predicted %A_e plots for Eq. 1–3 are illustrated in suppl. figures 1a–c, respectively. Moreover, grouping of compounds according to ion-status and ROC-LUE/ ROC-HUE yielded results similar to the above three equations (R²_adj. <0.5). Results of stepwise multiple linear regression indicted cLogP was the only parameter chosen by the model. Moreover, inclusion of other parameters (i.e. ACD labs cLogP/cLogD, PSA, MW, etc.) did not improve the prediction power of the regression models in all cases (R²_adj. <0.5) (not shown). Thus, our analysis indicated that simple physicochemical properties of compounds cannot be used to quantitatively predict the value of %A_e in humans.

Evaluation of physicochemical space

Analysis of the physicochemical spaces of compounds in ROC-LUE and ROC-HUE, as illustrated in figure 2, showed that there was a significant overlap between the physicochemical spaces of compounds in the two groups. In other words, compounds undergoing varying degree of UE have similar physicochemical space.

Figure 2.

Analysis of physicochemical space of compounds in ROC-LUE and ROC-HUE groups.

External validation

In order to evaluate the robustness of our methods, we compiled %A_e, cLogP, ACD labs cLogP, and ACD labs cLogD_(pH=7.4) data on 90 FDA approved NMEs between 2011 and 2016 as NMEs prior to these years were incorporated in the original dataset (834 compounds). We were able to correctly classify 87% of compounds (78 out of 90) using the two cut-off values for at least one of the three parameters and 83% of compounds (75 out of 90) using any two parameters (cLogP or ACD labs cLogP and cLogD). Moreover, only two compounds, tedizolid phosphate (cLogP=0.97) and ezogabine (ACD labs cLogP=0.81), have parameter values between the two-cut off values 0.7<cLogP/ ACD labs cLogP<1. Moreover, we applied Eq. 1–3 to predict %A_e of the 90 compounds in the validation set. The observed vs. predicted %A_e plots were superimposed on the respective plots for 834 compounds as illustrated in suppl. figures 2a–c. The R²_adj. values for %A_e of the 90 compounds predicted by cLogP, ACD labs cLogP, and ACD labs cLogD_(pH=7.4) are 0.35, 0.27, and 0.32, respectively. The results indicate the three physicochemical parameters are poor quantitative predictors of %A_e.

DISCUSSION

In the present study, we determined the quantitative threshold of extent of UE to be 16.8% and evaluated cLogP, ACD labs cLogP, and ACD labs cLogD_(pH=7.4) as the indicators of the extent of UE in humans. In BDDCS, the quantitative threshold for extensive/poor metabolism is 70%, and compounds in BDDCS classes 3 and 4 are likely to undergo biliary and urinary excretion [7]. We recommend the use of the reported MW threshold value (475 Da) and quantitative models for the prediction of biliary clearance for NMEs [11]. Note that we do not propose the extent of UE as a surrogate for the extent of metabolism [6, 7].

One limitation to the application of cLogP/ ACD labs cLogP and/or ACD labs cLogD as the indicators of the extent of UE for NMEs is that extent of UE cannot be determined for compounds that have cLogP/ ACD labs cLogP values between 0.7 and 1, and/or ACD labs cLogD_(pH=7.4) values between 0 and 0.5. However, our analysis indicated this does not appear to be a significant limitation for 90 NMEs that were approved in last 5 years as only two compounds had cLogP/ ACD labs CLogP values between 0.7 and 1, namely, tedizolid phosphate and ezogabine. The most significant contributor to this limitation was the overlapping physicochemical space of compounds undergoing high and low UE. Therefore, a priori determination of extent of UE using single ROC curve threshold or single cut-off value of physicochemical parameters (i.e. cLogP or cLogD) could not be achieved. Moreover, %A_e of compounds also cannot be quantitatively predicted by the simple physicochemical properties of these compounds.

We emphasize that the overall goal of our findings is to provide potential guidelines indicative of the extent of UE for NMEs. Of 90 small molecule NMEs approved by FDA in the past five years, 87% NMEs were correctly classified, which demonstrated significant robustness of the methods presented herein. Figure 3 illustrates the application of our findings in determination of the extent of UE of NMEs in humans.

Figure 3.

Summary of important findings and their potential application in the drug discovery and development of NMEs

CONCLUSION

Our findings in the present study indicate (1) a quantitative threshold of A_e=16.8% for high/ low extent of urinary excretion of compounds (N = 834) using ROC curve analysis; (2) cLogP, ACD labs cLogP, and ACD labs cLogD_(pH=7.4) were important physiochemical indicators (though not a quantitative predictor of %A_e) of the extent of UE; (3) On average, 71% of compounds with cLogP/ACD labs cLogP ≤0.7 and/or ACDLabs cLogD (pH=7.4) ≤0 undergo high UE (>16.8%) and 76% of compounds with cLogP/ ACD labs cLogP ≥1.0 and/or cLogD (pH=7.4) ≥ 0.5 undergo low UE (≤16.8%); and (4) 87% of 90 NMEs approved between 2011–2016 were correctly classified using our approach. These observations will find application in the early classification of NMEs with respect to elimination by urinary excretion.