Inhibition of CYP3A by erythromycin: in vitro-in vivo correlation in rats.
The prediction of in vivo drug-drug interactions from in vitro enzyme inhibition parameters remains challenging, particularly when time-dependent inhibition occurs. This study was designed to examine the accuracy of in vitro-derived parameters for the prediction of inhibition of CYP3A by erythromycin (ERY). Chronically cannulated rats were used to estimate the reduction in in vivo and in vitro intrinsic clearance (CL(int)) of midazolam (MDZ) after single and multiple doses of ERY; in vitro recovery of CL(int) was determined at 1, 2, 3, and 4 days after discontinuation of ERY. Enzyme inhibition parameters (k(inact), K(I), and K(i)) of ERY were estimated in vitro by using untreated rat liver microsomes. In vivo enzyme kinetic analysis indicated that single and multiple doses of ERY (150 mg/kg i.v. infusion over 4 h) reduced MDZ CL(int) by reversible and irreversible mechanisms, respectively. CYP3A inactivation after multiple doses of ERY treatment reflected metabolic intermediate complex formation without a significant change in hepatic CYP3A2 mRNA. A physiologically based pharmacokinetic model of the interaction between ERY and MDZ predicted a 2.6-fold decrease in CYP3A activity after repeated ERY treatment using in vitro-estimated enzyme inhibition parameters and in vivo degradation half-life of the enzyme (20 + or - 6 h). The observed -fold decreases were 2.3-fold and 2.1-fold for the in vitro-estimated CYP3A activity and the in vivo CL(int), respectively. This study demonstrates that in vivo DDIs are predictable from in vitro data when the appropriate model and parameter estimates are available.
Departments of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana. zhangxx@lilly.com
Xin
X
Zhang
Raymond E
RE
Galinsky
Robert E
RE
Kimura
Sara K
SK
Quinney
David R
DR
Jones
Stephen D
SD
Hall
D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D055162:Biocatalysis / Q000187:drug effects; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D004917:Erythromycin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D065692:Cytochrome P-450 CYP3A Inhibitors; D008565:Membrane Proteins; C042940:4-hydroxymidazolam; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam