Table 7.
Detailed description of antihypertensive drugs metabolism according to the 3rd level E.C. classification of BNICE frame-work generalized reaction rules. The + indicates sequential reactions given by generalized reaction rules and the indicates alternative generalized reaction rules given the same metabolite.
| Category | Drug name | Metabolites | Enzymes | 3rd level E.C. number of BNICE generalized reaction rules |
|---|---|---|---|---|
| ACE Inhibitors | Benazepril | Benazeprilat | Carboxylesterases | 3.1.1.- |
| Benazeprilat glucuronic acid | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Captopril | Cysteine-captopril disulfide | 1.8.1.-|1.11.1.- | ||
| Capropril dimer disulfide | 1.8.1.-|1.11.1.- | |||
| Cilazapril | Cilazaprilat | Carboxylesterases | 3.1.1.- | |
| Enalapril | Enalaprilat | Carboxylesterases | 3.1.1.- | |
| Fosinopril | Fosinoprilat | Carboxylesterases | 3.1.1.- | |
| p-Hydroxy fosinopril metabolite | 1.14.13.- | |||
| Glucuronides of fosinopril | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Lisinopril | Not metabolized | |||
| Moexipril | Moexiprilat | Carboxylesterases | 3.1.1.- | |
| Perindopril | Perindoprilat | Carboxylesterases | 3.1.1.- | |
| Perindopril glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Perindoprilat glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Quinapril | Quinaprilat | Carboxylesterases | 3.1.1.- | |
| Ramipril | Ramiprilat | Carboxylesterases | 3.1.1.- | |
| Diketopiperazine ester | 3.5.1.- | |||
| Diketopiperazine acid | 3.5.1.- + 3.1.1.- | |||
| Glucuronides of ramipril | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Glucuronides of ramiprilat | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Rescinnamine | No information available | |||
| Spirapril | Spiraprilat | Carboxylesterases | 3.1.1.- | |
| Trandolapril | Trandolaprilat | Carboxylesterases | 3.1.1.- | |
| Diketopiperazine ester | 3.5.1.- | |||
| Diketopiperazine acid | 3.5.1.- + 3.1.1.- | |||
| Trandolapril glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Trandolaprilat glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Beta-blockers | Acebutolol | Diacetolol | CYP2D6 | 2.1.1.- + 2.1.1.- |
| Alprenolol | 4-Hydroxy-alprenolol | CYP2D6 | 1.14.13.- | |
| Atenolol | Not metabolized | |||
| Betaxolol | α-Hydroxy betaxolol | CYP1A2, CYP2D6 | 1.14.13.- | |
| Bisoprolol | Demethyl carboxylic acid | CYP3A4, CYP2D6 | 2.7.8.- +1.1.1.- +1.2.1.- | |
| Deethyl carboxylic acid | 2.7.8.- +1.1.1.- +1.2.1.- | |||
| Deethyl derivative | 2.7.8.- +1.1.1.- +1.2.1.- | |||
| Carvedilol | 8-Hydroxy carvedilol | CYP1A2, CYP3A4, CYP1A1 | 1.14.13.- | |
| 4'-Hydroxy carvedilol | CYP2D6, CYP2E1, CYP2C9 | 1.14.13.- | ||
| 5'-Hydroxy carvedilol | CYP2D6, CYP2E1, CYP2C9 | 1.14.13.- | ||
| O-Desmethyl carvedilol | CYP2C9, CYP2D6, CYP1A2, CYP2E1 | 1.14.13.- | ||
| 1-Hydroxy carvedilol | Prostaglandin G/H synthase 1 | 1.14.13.- | ||
| 4'-Hydroxyphenyl carvedilol | 1.14.13.- | |||
| Esmolol | Methanol | Esterases | 1.14.13.- | |
| Labetalol | 7 Glucuronides metabolites | UDP-Glucuronosyltransferase | 2.4.1B1 | |
| 3-Amino-1-phenyl butane | GI mucosa | 1.4.1.-|1.4.3.-|1.5.99.-|4.3.1.- | ||
| 3-Amino-1-(4-hydroxyphenyl) butane | GI mucosa | 1.4.1.-|1.4.3.-|1.5.99.-|4.3.1.- | ||
| Benzyl acetone | GI mucosa | 1.4.1.-|1.4.3.-|1.5.99.-|4.3.1.- | ||
| Metoprolol | α-Hydroxy metoprolol | CYP2D6 | 1.14.13.- | |
| Nadolol | Not metabolized | |||
| Nebivolol | Hydroxy alicyclic metabolites | CYP2D6 | 1.14.13.- | |
| Hydroxy aromatic metabolites | CYP2D6 | 1.14.13.- | ||
| 1st generation glucuronides | UDP-Glucuronosyltransferase | 2.4.1B1 | ||
| N-dealkylation | CYP2D6 | 1.4.1.-|1.4.3.-|1.5.99.-|4.3.1.- | ||
| 2nd generation glucuronides (after the hydroxylation) | UDP-Glucuronosyltransferase | 1.14.13.- +2.4.1.- | ||
| Oxprenolol | Glucuronides of unchanged oxprenolol | UDP-Glucuronosyltransferase | 2.4.1.- | |
| Hydroxylation to the aromatic ring of unchanged oxprenolol | CYP2D6 | 1.14.13.- | ||
| Glucuronides of hydroxylated oxprenolol | UDP-Glucuronosyltransferase | 1.14.13.- +2.4.1.- | ||
| N-dealkylation, producing the hydroxy carboxylic acid | CYP2D6 | 1.4.1.-|1.4.3.- + 1.1.1.- | ||
| Carbinol | CYP2D6 | 1.4.1.-|1.4.3.- | ||
| Monoallyl ether of catechol | CYP2D6 | 3.3.1.- | ||
| Penbutolol | Glucuronide metabolite | UDP-Glucuronosyltransferase | 2.4.1.- | |
| 4-Hydroxy metabolite | 1.14.13.- | |||
| Pindolol | Hydroxylated metabolites | 1.14.13.- | ||
| Glucuronides of hydroxylated metabolites | UDP-Glucuronosyltransferase | 1.14.13.- + 2.4.1.- | ||
| Sulfate metabolites | Sulfotransferases | 1.14.13.- | ||
| Propanolol | N-Desisopropyl propranolol | CYP1A2 | 1.4.1.-|1.4.3.- | |
| 4'-Hydroxy propanolol | CYP2D6 | 1.14.13.- | ||
| Calcium Channel Blockers | Amlodipine | Pyridine derivative | CYP3A4 | 5.3.3.-|1.3.1.-+1.5.3.-|1.5.1.- |
| De-amino amlodipine | CYP3A4 | 1.4.3.-|1.5.99.- | ||
| Ester hydrolysis of the S-methoxycarbonyl group | Carboxylesterases | 3.1.1.- | ||
| Amlodipine glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Diltiazem | N-desmethyl diltiazem | CYP3A4 | 1.4.3.-|1.5.99.- | |
| O-desacetyl-N-desmethyl diltiazem | CYP3A4 | 1.4.3.-|1.5.99.-+1.14.13.-|3.1.1.- | ||
| Felodipine | Dehydro felodipine | CYP3A4 | 5.3.3.-|1.3.1.-+1.5.3.-|1.5.1.- +3.1.1.-+.1.14.13.- | |
| Isradipine | Pyridine of isradipine | CYP3A4 | 5.3.3.-. + 1.5.1.-|1.5.3.- | |
| Carboxylic acid of isradipine | CYP3A4 | 3.1.1.- | ||
| Carboxylic acid of isradipine pyridine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.-+3.1.1.- | ||
| Nifedipine | Pyridine of nifedipine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- | |
| Carboxylic acid of nifedipine | CYP3A4 | 3.1.1.- | ||
| Carboxylic acid of nifedine pyridine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.-+3.1.1.- | ||
| Nimodipine | Dehydro nimopidine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- | |
| Carboxylic acid of nimopidine | CYP3A4 | 3.1.1.- | ||
| Cardoxylic acid of dehydro nimopidine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.-+3.1.1.- | ||
| Nisoldipine | Hydroxylation of the isobutyl moiety | CYP3A4 | 1.14.13.- | |
| Dehydrogenation of the 1, 4-dihydropyridine system | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- | ||
| Oxidative ester cleavage | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.-+3.1.1.- | ||
| Hydroxylation of one of the methyl groups in 2-position and subsequent oxidation to the carboxylic acid | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- + 1.14.13.- | ||
| Hydroxylation of one of the methyl groups in 6-position and subsequent oxidation to the carboxylic acid | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- + 1.14.13.- | ||
| Oxidation of one of the methyl groups of the isobutyl moiety to the carboxyl group reduction of the aromatic nitro group | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- + 1.1.1.- | ||
| Glucuronidation | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Nitrendipine | Dehydro nitredipine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.- | |
| Carboxylic acid of nitrendipine | CYP3A4 | 3.1.1.- | ||
| Cardoxylic acid of dehydro nitrendipine | CYP3A4 | 5.3.3.- + 1.5.1.-|1.5.3.-+3.1.1.- | ||
| Verapamil | O-Desmethyl verapamil | 1.14.13.- | ||
| O-Desmethyl verapamil (D-702) | CYP2C8, CYP2C18, CYP2C9 | 1.14.13.- | ||
| O-Desmethyl verapamil (D-703) | CYP2C8, CYP2C9 | 1.14.13.- | ||
| Category | Drug name | Metabolites | Enzymes | 3rd level E.C. number of BNICE generalized reaction rules |
| Norverapamil | CYP2C8, CYP3A4, CYP3A5, CYP1A2 | 1.4.3.-|1.5.99.- | ||
| D-617 | CYP2C8 | 1.4.1.-|1.4.3.-|1.5.99.- | ||
| K+ sparing diuretics | Amiloride | Not metabolized | ||
| Eplerenone | 21-Hydroxy eplererone | CYP3A4 | 1.14.13.- | |
| 6b-Hydroxy elpererone | CYP3A4 | 1.14.13.- | ||
| 6b, 21-Dihydroxy elpererone | CYP3A4 | 1.14.13.-+1.14.13.- | ||
| 3a, 6b-Dihydroxy elpererone | CYP3A4 | 1.1.1.- + 1.14.13.- | ||
| 6b, 15a-Dihydroxy elpererone | CYP3A4 | 1.14.13.-+1.14.13.- | ||
| 3a, 6b, 21-Trihydroxy elpererone | CYP3A4 | 1.1.1.- + 1.14.13.- +1.14.13.- | ||
| 2a, 3b, 6b-Trihydroxy elpererone | CYP3A4 | 1.1.1.- + 1.14.13.- +1.14.13.- | ||
| Spironolactone | Spironolactone-thiole | 1.2.1.-|2.3.1.-|3.1.2.- | ||
| Spironolactone-dethioacetate | 1.2.1.-|2.3.1.-|3.1.2.-+3.3.1.-+4.2.1.-+1.3.1.- | |||
| Canrenone | 1.2.1.-|2.3.1.-|3.1.2.-+3.3.1.- +4.2.1.- | |||
| Thio-methyl-spironolactone | 1.2.1.-|2.3.1.-|3.1.2.- + 2.1.1.- | |||
| Hydroxyl-thiomethyl-spironolactone | 1.2.1.-|2.3.1.-|3.1.2.-+2.1.1.-+1.14.13A1 | |||
| Triamterene | 4-Hydroxy triamterene | CYP1A2 | 1.14.13.- | |
| 4-Hydroxy-sulfate-triamterene | Sulfotransferases | 1.14.13.- + 2.8.2.- | ||
| Loop Diuretics | Bumetanide | Debutylbumetanide | 1.4.1.-|1.4.3.-|4.3.1.- | |
| Alpha-hydroxy bumetanide | 1.14.13.-|1.14.18.-|1.17.99.- | |||
| Bumetanide carboxylic acid | 1.13.11.- | |||
| Bumetanide glucuronides | UDP-Glucuronosyltransferase | 2.4.1.- | ||
| Ethacrynic acid | Glutathione conjugation | Glutathione-S-transferases | 2.5.1.- | |
| Mercapturic Acid | 2.5.1.-+3.5.1.- | |||
| Furosemide | 4-Chloro-5-sulfamoyl anthranilic acid | 2.4.1.- | ||
| Torasemide | Hydroxylation of the methyl group of the benzyl ring | CYP2C8, CYP2C9 | 1.14.13.-|1.17.99.- | |
| M1 carboxylic acid | CYP2C8, CYP2C9 | 1.13.11.- | ||
| 4-Hydroxy torasemide | CYP2C8, CYP2C9 | 1.14.13.- | ||
| Thiazide Diuretics | Bendroflumethiazide | No available information | ||
| Chlorothiazide | Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. | |||
| Cyclothiazide | No available information | |||
| Hydrochlorothiazide | Hydrochlorothiazide is not metabolized. | |||
| Hydroflumethiazide | Essentially unchanged | |||
| Methyclothiazide | No information available | |||
| Polythiazide | No information available | |||
| Quinethazone | No information available | |||
| Trichlormethiazide | No information available | |||
| Thiazide-like Diuretics | Chlorthalidone | Excreted unchanged in the urine | ||
| Indapamide | Hydroxyl-indapamide | CYP3A4 | 1.14.13.- | |
| Dehydro-indapamide | CYP3A4 | 1.14.13.-|1.14.15.-|1.1.1.- | ||
| Hydroxyl-dehydro-Indapamide | CYP3A4 | 1.14.13.-|1.14.15.-|1.1.1.- + 1.14.13.- | ||
| Indapamide-epoxide | Microsomal epoxide hydrolase | 1.3.1.-|1.5.3.-|1.14.19.- | ||
| Dihydroxy-indapamide | CYP3A4 | 1.14.12.- | ||
| Indapamide-glutathione conjugation | Glutathione (non enzymatic) | 1.14.12.- + 2.5.1.- | ||
| Metolazone | Excreted unchanged in the urine |