![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 26, Issue 2, 110-114, February 1998
Department of Anesthesia (C.W., H.B., K.W., S.N., E.M.),
Division
of Clinical Pharmacology (J.X.d.V., R.D., I.W.-S.), and
Department of
Pathology (W.H.),
Ruprecht-Karls-University, and Department of
Pharmacology and Toxicology, Friedrich-Alexander-University (R.H.B.,
B.K.)
It was recently shown by others that the clearance of midazolam/kg
body weight after iv administration correlates with hepatic cytochrome
P450 (CYP or P450) 3A content in liver transplant patients. However,
after po administration midazolam undergoes significant first-pass
metabolism, with significant intestinal extraction. The relationship
between hepatic CYP3A and midazolam disposition after po administration
had not previously been investigated. The aim of this study was to
compare intraindividually hepatic CYP3A content and activity with the
in vivo pharmacokinetics of midazolam (7.5 mg) administered
po. For 15 patients scheduled for partial liver resection, the AUC
values for the observed time period (AUC0-5hr)
and to infinity (AUCinf) and the clearance were
determined. In a macroscopically normal area of resected liver tissue,
the microsomal CYP3A4 content (nanomoles per nanomole of total P450)
was measured by immunoblot analysis and parameters (apparent
Vmax, apparent
KM, and intrinsic clearance) for the microsomal 
-hydroxylation of midazolam were determined. Clearance/kg in vivo correlated with the apparent
Vmax (r2 = 0.45, p < 0.01) and the CYP3A4 content
(r2 = 0.29, p < 0.05).
We conclude that interindividual variability in the pharmacokinetics of
po administered midazolam is in part determined by interindividual
variability in the hepatic microsomal Vmax for the -hydroxylation of
midazolam. However, the relationship between the disposition of
midazolam administered po and hepatic CYP3A content is weaker than that
reported after iv administration, indicating the importance of the
contribution of intestinal CYP3A to the in vivo disposition
of midazolam administered po.
This article has been cited by other articles:
|
|
 |
|
  H. F. Perrett, Z. E. Barter, B. C. Jones, H. Yamazaki, G. T. Tucker, and A. Rostami-Hodjegan Disparity in Holoprotein/Apoprotein Ratios of Different Standards Used for Immunoquantification of Hepatic Cytochrome P450 Enzymes Drug Metab. Dispos., October 1, 2007; 35(10): 1733 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Xie, L. H. Tan, E. C. Polasek, C. Hong, M. Teillol-Foo, T. Gordi, A. Sharma, D. J. Nickens, T. Arakawa, D. W. Knuth, et al. CYP3A and P-Glycoprotein Activity Induction With St. John's Wort in Healthy Volunteers From 6 Ethnic Populations J. Clin. Pharmacol., March 1, 2005; 45(3): 352 - 356. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
K. C. Patki, L. L. von Moltke, and D. J. Greenblatt IN VITRO METABOLISM OF MIDAZOLAM, TRIAZOLAM, NIFEDIPINE, AND TESTOSTERONE BY HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROMES P450: ROLE OF CYP3A4 AND CYP3A5 Drug Metab. Dispos., July 1, 2003; 31(7): 938 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Weaver, K. S. Graham, I. G. Beattie, and R. J. Riley CYTOCHROME P450 INHIBITION USING RECOMBINANT PROTEINS AND MASS SPECTROMETRY/MULTIPLE REACTION MONITORING TECHNOLOGY IN A CASSETTE INCUBATION Drug Metab. Dispos., July 1, 2003; 31(7): 955 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Westlind-Johnsson, S. Malmebo, A. Johansson, C. Otter, T. B. Andersson, I. Johansson, R. J. Edwards, A. R. Boobis, and M. Ingelman-Sundberg COMPARATIVE ANALYSIS OF CYP3A EXPRESSION IN HUMAN LIVER SUGGESTS ONLY A MINOR ROLE FOR CYP3A5 IN DRUG METABOLISM Drug Metab. Dispos., June 1, 2003; 31(6): 755 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-S. Shih and J.-D. Huang Pharmacokinetics of Midazolam and 1'-Hydroxymidazolam in Chinese with Different CYP3A5 Genotypes Drug Metab. Dispos., December 1, 2002; 30(12): 1491 - 1496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamano, K. Yamamoto, M. Katashima, H. Kotaki, S. Takedomi, H. Matsuo, H. Ohtani, Y. Sawada, and T. Iga Prediction of Midazolam{---}cyp3a Inhibitors Interaction in the Human Liver from in Vivo/in Vitro Absorption, Distribution, and Metabolism Data Drug Metab. Dispos., April 1, 2001; 29(4): 443 - 452. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. D. Perloff, L. L. von Moltke, M. H. Court, T. Kotegawa, R. I. Shader, and D. J. Greenblatt Midazolam and Triazolam Biotransformation in Mouse and Human Liver Microsomes: Relative Contribution of CYP3A and CYP2C Isoforms J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 618 - 628. [Abstract] [Full Text]
|
|
|
|
|
|
W. Jäger, M. A. Correia, L. M. Bornheim, A. Mahnke, W. G. Hanstein, L. Xue, and L. Z. Benet Ethynylestradiol-Mediated Induction of Hepatic CYP3A9 in Female Rats: Implication for Cyclosporine Metabolism Drug Metab. Dispos., December 1, 1999; 27(12): 1505 - 1511. [Abstract] [Full Text]
|
|
|
|
|
|
S. Kumar, K. W. Riggs, and D. W. Rurak Role of the Liver and Gut in Systemic Diphenhydramine Clearance in Adult Nonpregnant Sheep Drug Metab. Dispos., February 1, 1999; 27(2): 297 - 302. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
