CYP2C8 activity recovers within 96 hours after gemfibrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe.
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.
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finlandjanne.backman@helsinki.fi
Janne T
JT
Backman
Johanna
J
Honkalammi
Mikko
M
Neuvonen
Kaisa J
KJ
Kurkinen
Aleksi
A
Tornio
Mikko
M
Niemi
Pertti J
PJ
Neuvonen
D000284:Administration, Oral; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D001786:Blood Glucose / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D015248:Gemfibrozil / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D005838:Genotype; D005965:Glucuronates / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008954:Models, Biological; D015335:Molecular Probes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
D001786:Blood Glucose; D002219:Carbamates; D004791:Enzyme Inhibitors; D005965:Glucuronates; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D015335:Molecular Probes; D027361:Organic Anion Transporters; D010880:Piperidines; C503999:SLCO1B1 protein, human; C072379:repaglinide; C094370:gemfibrozil 1-O-acylglucuronide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil