DMD Large equally mixed donor pool

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yao, C.
Right arrow Articles by Levy, R. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yao, C.
Right arrow Articles by Levy, R. H.

Vol. 31, Issue 5, 565-571, May 2003

Comparison of In Vitro and In Vivo Inhibition Potencies of Fluvoxamine toward CYP2C19

Caiping Yao, Kent L. Kunze, William F. Trager, Evan D. Kharasch, and René H. Levy

Departments of Pharmaceutics (C.Y., R.H.L.), Medicinal Chemistry (K.L.K., W.F.T., E.D.K.), Anesthesiology (E.D.K.), and Neurological Surgery (R.H.L.), University of Washington, Seattle, Washington

A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (Ki) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe. Ki values based on total added fluvoxamine concentration (Ki,total) and unbound fluvoxamine concentration (Ki,ub) were calculated, and interindividual variability in Ki values was examined in six nonfatty livers. Ki,total values varied with microsomal protein concentration, whereas the corresponding Ki,ub values were within a narrow range (70-80 nM). In vivo inhibition constants (Kiiv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (r2 = 0.88, p < 0.001). The mean (±S.D.) values of Kiiv based on total and unbound plasma concentrations were 13.5 ± 5.6 and 1.9 ± 1.1 nM, respectively. Comparison of in vitro and in vivo Ki values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
N. Isoherranen, S. R. Ludington, R. C. Givens, J. K. Lamba, S. N. Pusek, E. C. Dees, D. K. Blough, K. Iwanaga, R. L. Hawke, E. G. Schuetz, et al.
The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation
Drug Metab. Dispos., January 1, 2008; 36(1): 146 - 154.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Di Marco, A. Cellucci, A. Chaudhary, M. Fonsi, and R. Laufer
High-Throughput Radiometric CYP2C19 Inhibition Assay Using Tritiated (S)-Mephenytoin
Drug Metab. Dispos., October 1, 2007; 35(10): 1737 - 1743.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
S. Sudsakorn, J. Skell, D. A. Williams, T. J. O'Shea, and H. Liu
Evaluation of 3-O-Methylfluorescein as a Selective Fluorometric Substrate for CYP2C19 in Human Liver Microsomes
Drug Metab. Dispos., June 1, 2007; 35(6): 841 - 847.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. Venkatakrishnan and R. S. Obach
IN VITRO-IN VIVO EXTRAPOLATION OF CYP2D6 INACTIVATION BY PAROXETINE: PREDICTION OF NONSTATIONARY PHARMACOKINETICS AND DRUG INTERACTION MAGNITUDE
Drug Metab. Dispos., June 1, 2005; 33(6): 845 - 852.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
R. L. Walsky and R. S. Obach
VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES
Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
H. M. Jones, D. Hallifax, and J. B. Houston
QUANTITATIVE PREDICTION OF THE IN VIVO INHIBITION OF DIAZEPAM METABOLISM BY OMEPRAZOLE USING RAT LIVER MICROSOMES AND HEPATOCYTES
Drug Metab. Dispos., May 1, 2004; 32(5): 572 - 580.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
M. H. Court, S. Krishnaswamy, Q. Hao, S. X. Duan, C. J. Patten, L. L. von Moltke, and D. J. Greenblatt
EVALUATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE, MORPHINE, AND CODEINE AS PROBE SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 2B7 (UGT2B7) IN HUMAN LIVER MICROSOMES: SPECIFICITY AND INFLUENCE OF THE UGT2B7*2 POLYMORPHISM
Drug Metab. Dispos., September 1, 2003; 31(9): 1125 - 1133.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. M. Neal, K. L. Kunze, R. H. Levy, R. A. O'Reilly, and W. F. Trager
KIIV, AN IN VIVO PARAMETER FOR PREDICTING THE MAGNITUDE OF A DRUG INTERACTION ARISING FROM COMPETITIVE ENZYME INHIBITION
Drug Metab. Dispos., August 1, 2003; 31(8): 1043 - 1048.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics.