D. Elsherbiny(1), S. Asimus(2), M. Ashton(2), U. S. H. Simonsson(1)
(1)Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, BMC, 751 24 Uppsala, Sweden; (2) Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy at Göteborg University, Box 431, 405 30 Gothenburg, Sweden.
Objectives: The aim of this study was to develop a model to describe the pharmacokinetics of S-mephenytoin, a probe of CYP2B6 and CYP2C19 activities, and its metabolites S-nirvanol and S-4-hydroxymephenytoin in healthy volunteers.
Methods: The population pharmacokinetics of S-mephenytoin and its metabolites were described by nonlinear mixed effects modeling using NONMEM. Data were pooled from two studies. One dataset contained rich data from 14 healthy male volunteers, who had received a single oral dose of 200 mg racemic mephenytoin. The second dataset contained sparse data from 74 healthy volunteers, who had received a single oral dose of 100 mg racemic mephenytoin.
Results: The pharmacokinetics of S-mephenytoin and its metabolites were described by multi-compartment models incorporating first-pass formation of S-4-hydroxymephenytoin.
The final model contained estimation of three subpopulations using the $MIXTURE subroutine. The formation clearance of S-4-hydroxymephenytoin was estimated separately for the extensive metabolizers (EMs), intermediate metabolizers (IMs) and was fixed to zero in poor metabolizers (PMs). S-4-hydroxymephenytoin first-pass formation was estimated only for EMs. Bioavailability of mephenytoin was fixed to 1 for PMs and was estimated relative to PMs in the rest of the population. The percentage of subjects estimated to be EMs, IMs and PMs were about 70, 13 and 17%, respectively, which is consistent with literature reports of the distribution in Asians.
The population estimate of mephenytoin bioavailability was about three fold lower in EMs and IMs compared to PMs. The formation clearance of S-4-hydroxymephenytoin was about 2 fold higher in EMs compared to IMs.
Conclusion: The presented model adequately describes the population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4-hydroxymephenytoin and confirms the presence of the three subpopulations of CYP2C19 phenotype described in the literature. This model will be developed to be able to assess the inductive/inhibitory effect of CYP2B6 and CYP2C19 activity by various drugs.
Reference: PAGE 14 () Abstr 823 [www.page-meeting.org/?abstract=823]
Poster: poster