Table 2.

Indirect metabolism of drugs by gut bacteria associated with pharmacokinetic changes

Indirect metabolism
Drug	Animal/human	In vivo/in vitro	Effect on PK (intact gut microbiome)	Enzyme	Diversity	Comments
Acetaminophen [35]	Animal	In vivo	↑ AUC and Cmax	SULT1A1	N/A	P-cresol competes with acetaminophen binding to SULT1A1 → prevents host from detoxifying acetaminophen
Caffeine [33]	Human	In vivo	↓ CL	CYP1A2	↓ α ↑ β	Decreased CYP activity when treated with cefprozil
Metformin [36]	Animal	In vivo	↓ Cmax and ↑ half-life	Oct1	N/A	Pharmacokinetic changes likely owing to ↓ Oct1 expression in the liver → altered hepatic uptake of metformin in vivo
Midazolam [33, 37]	Animal Human	In vitro In vivo	↓ Cmax, AUC, and half-life four-fold ↓ CL	CYP3A; UGT	N/A ↓ α ↑ β	Low levels of CYP3A activity in GF mice decrease drug metabolism in vivo Decreased CYP activity when treated with cefprozil
Omeprazole [33]	Human	In vivo	↓ AUC metabolite ratio	CYP2C19	↓ α ↑ β	Decreased CYP activity when treated with cefprozil
Progestogens [38]	Human	In vivo	MPA had longest half-life	CYP450	N/A	Hydroxylation of progestins are likely CYP450 mediated
Triazolam [13, 39]	Animal	In vivo	Increased metabolite-to-parent drug ratio in SPF vs GF mice	CYP3A CYP3A11 CYP3A25	N/A	CYP activity higher for the livers of SPF mice (Bacteroides and Escherichia coli) Ciprofloxacin administration to SPF mice → significant ↓ mRNA expression of CYP3A11 in the liver

AUC area under the concentration–time curve, CL clearance, C_max maximum concentration, CYP cytochrome P450, GF germ-free, mRNA messenger RNA, N/A not available, Oct1 organic cation transporter 1, PK pharmacokinetics, SPF specific pathogen-free, SULT1A1 sulfotransferase 1A1, UGT uridine diphosphate glucuronosyltransferase (animal), ↑ increased, ↓ decreased