Table 2.

Characteristics of possible index substrates of CYP enzymes

Enzyme	Substrate	Sensitivitya	Other relevant enzymes/transporters	F	t1/2 (h)	Remarks	E/Fb
CYP1A2	Agomelatine	++++		0.05	1–2	Limited availability in some countries
	Caffeined	++++	NAT, XO	1.00	3–7		E/F
	Melatonin	++++	CYP1A1c	0.03	0.9
	Theophylline	++	CYP3A4, CYP2E1	0.96	9	Adverse effects at high concentrations	E
	Tizanidined	++++		0.34	2.5	Adverse effects at high concentrations	F
CYP2B6	Bupropiond	+	11β‐HSD1c	0.9	11	Hydroxybupropion to bupropion AUC ratio is a selective and more sensitive marker of CYP2B6 than bupropion AUC	E
	(S)‐Ketamine	++	CYP3A4	0.08	2–6	Parenteral formulation can be given orally
	Efavirenz	N/A (++)	CYP2A6	N/A	52–76	Limited DDI data	E
CYP2C8	Amodiaquine	N/A		N/A	5	Limited DDI data Limited availability Metabolite t1/2 > 100 hours	E
	Daprodustat	++++		N/A	1	Limited DDI data Limited availability, currently in phase III
	Dasabuvird	++++	CYP3A4	0.70	5.5–6
	Repaglinided	+++	CYP3A4, OATP1B1	0.56	0.8	Adverse effects at high concentrations	E/F
CYP2C9	(S)‐Warfarin	++ (+++)		0.93 (racemic)	21–43	Bleeding risk	E/F
	Flurbiprofen	++		0.92	5.5	4′‐Hydroxyflurbiprofen/flurbiprofen ratio is a sensitive marker of CYP2C9 Limited availability of appropriate formulation
	Fluvastatind	+ (++)	OATP1B1	0.29	0.7
	Tolbutamided	++ (+++)		0.8–0.9	5.9	Limited availability Adverse effects at high concentrations	E/F
CYP2C19	Lansoprazole	++ (+++)	CYP3A4	0.81	0.9	Delayed absorption	F
	Omeprazoled	+++ (++++)	CYP3A4	0.53	0.7	Delayed absorption Inhibitor of CYP2C19	E/F
	Pantoprazoled	N/A (+++)		0.77	1.0	Delayed absorption Breath test established
	Rabeprazole	++ (+++)	CYP3A4	0.52	1.5	Delayed absorption
CYP2D6	Desipramine	+++ (+++)	CYP3A4	0.38	28	Limited availability in some countries	E/F
	Dextromethorphand	++++ (++++)	CYP3A4	N/A	3.4	Dextrorphan/dextromethorphan ratio used as the index	F
	Metoprolol	++ (+++)	CYP3A4	0.38	3.2		E
	Nebivolol	+++ (++++)	CYP2C19	N/A	11		F
	Tolterodine	++++ (++++)	CYP3A4	0.26 (NMs)	2.3 (NMs)
CYP3A4	Buspirone	++++		0.04	2.4	Sensitive to intestinal CYP3A4 inhibition
	Midazolamd	++++		0.44	1.9	i.v. formulation available to assess hepatic CYP3A4 Adverse effects at high concentrations	E/F
	Sildenafil	++++	CYP2C9	0.38	2.4
	Simvastatin (lactone)d	++++		< 0.05	2–3	Simvastatin acid substrate of OATP1B1 Sensitive to intestinal CYP3A4 inhibition
	Triazolam	++++		0.44	2.9	Adverse effects at high concentrations	F

The table contains all the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)‐recommended index substrates and some selected alternatives based on potential advantages in sensitivity, selectivity, and/or relative safety. The data are compiled primarily from the UW Metabolism and Transport Drug Interaction Database (Copyright University of Washington 1999–2019. Accessed: January−February 2019), secondarily from drug labels.

AUC, area under plasma concentration‐time curve; CYP, cytochrome P450; E/F, European Medicines Agency/US Food and Drug Administration; F, bioavailability; HSD‐1, hydroxysteroid dehydrogenase type 1; NAT, N‐acetyl transferase; NMs, normal metabolizers; N/A, not available; OATP, organic anion‐transporting polypeptide; t_1/2, elimination half‐life; XO, xanthine oxidase.

^aIndication of sensitivity is based on data from a trial with an EMA/FDA‐recommended index inhibitor of the affected CYP. In some cases, a second sensitivity value is given within brackets, based on pharmacogenetic data. Classification: ++++ a maximal > 10‐fold increase in AUC, +++ a maximal 5–10‐fold increase, ++ a maximal two to fivefold increase, + a maximal 1.25−2‐fold increase. Values for maximal fold increases in AUC are given in Table S1 .

^bIndicates if the drug is recommended as a clinical CYP probe substrate by the EMA (E) and/or the FDA (F) (2–3).

^cBased on in vitro data only.

^dOur recommended substrate.