Abstract
Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.
Publication types
-
Randomized Controlled Trial
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Administration, Oral
-
Area Under Curve
-
Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
-
Aryl Hydrocarbon Hydroxylases / genetics
-
Aryl Hydrocarbon Hydroxylases / metabolism*
-
Biotransformation
-
Blood Glucose / drug effects
-
Carbamates / administration & dosage
-
Carbamates / blood
-
Carbamates / pharmacokinetics*
-
Cross-Over Studies
-
Cytochrome P-450 CYP2C8
-
Drug Interactions
-
Enzyme Inhibitors / administration & dosage*
-
Enzyme Inhibitors / blood
-
Enzyme Inhibitors / pharmacokinetics
-
Female
-
Gemfibrozil / administration & dosage*
-
Gemfibrozil / analogs & derivatives
-
Gemfibrozil / blood
-
Gemfibrozil / pharmacokinetics
-
Genotype
-
Glucuronates / blood
-
Glucuronates / pharmacokinetics
-
Half-Life
-
Humans
-
Hypoglycemic Agents / administration & dosage
-
Hypoglycemic Agents / blood
-
Hypoglycemic Agents / pharmacokinetics*
-
Hypolipidemic Agents / administration & dosage*
-
Hypolipidemic Agents / blood
-
Hypolipidemic Agents / pharmacokinetics
-
Liver-Specific Organic Anion Transporter 1
-
Male
-
Models, Biological
-
Molecular Probes / administration & dosage
-
Molecular Probes / blood
-
Molecular Probes / pharmacokinetics*
-
Organic Anion Transporters / genetics
-
Organic Anion Transporters / metabolism
-
Phenotype
-
Piperidines / administration & dosage
-
Piperidines / blood
-
Piperidines / pharmacokinetics*
-
Young Adult
Substances
-
Blood Glucose
-
Carbamates
-
Enzyme Inhibitors
-
Glucuronates
-
Hypoglycemic Agents
-
Hypolipidemic Agents
-
Liver-Specific Organic Anion Transporter 1
-
Molecular Probes
-
Organic Anion Transporters
-
Piperidines
-
SLCO1B1 protein, human
-
repaglinide
-
gemfibrozil 1-O-acylglucuronide
-
Aryl Hydrocarbon Hydroxylases
-
CYP2C8 protein, human
-
Cytochrome P-450 CYP2C8
-
Gemfibrozil