An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation

Bradley S. Mayhew, David R. Jones And, Stephen D. Hall

Research output: Contribution to journalArticle

243 Citations (Scopus)

Abstract

An in vitro model is proposed to account for the clinically observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic activity resulting from metabolic intermediate complex formation and the concentration dependencies thereof were determined in vitro for clarithromycin, fluoxetine, and N-desmethyl diltiazem, which is the primary metabolite of diltiazem. Using the in vitro concentration-dependent rates for loss of activity, in vivo rates of CYP3A4 inactivation were predicted for these compounds at a clinically relevant unbound plasma concentration of 0.1 μM. Based on the predicted rates combined with published rates for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the steady-state concentration of liver CYP3A4 to approximately 72, 39, or 21% of initial levels, respectively. These reductions correspond to 1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the plasma concentration-time curve of a coadministered drug that is eliminated exclusively by hepatic CYP3A4 metabolism. These predicted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primary metabolite of diltiazem, at clinically relevant concentrations, inactivate CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentrations of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated mechanistic inactivation of CYPs play a major role in many clinically observed drug-drug interactions.

Original languageEnglish
Pages (from-to)1031-1037
Number of pages7
JournalDrug Metabolism and Disposition
Volume28
Issue number9
StatePublished - 2000

Fingerprint

Cytochrome P-450 CYP3A
Diltiazem
Clarithromycin
Fluoxetine
Metabolites
Drug interactions
Plasmas
In Vitro Techniques
Liver
Drug Interactions
Metabolism
Pharmaceutical Preparations
Degradation
Substrates

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. / Mayhew, Bradley S.; Jones And, David R.; Hall, Stephen D.

In: Drug Metabolism and Disposition, Vol. 28, No. 9, 2000, p. 1031-1037.

Research output: Contribution to journalArticle

Mayhew, Bradley S. ; Jones And, David R. ; Hall, Stephen D. / An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. In: Drug Metabolism and Disposition. 2000 ; Vol. 28, No. 9. pp. 1031-1037.
@article{6c7389b24d4e4dc8a6336a680044cc06,
title = "An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation",
abstract = "An in vitro model is proposed to account for the clinically observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic activity resulting from metabolic intermediate complex formation and the concentration dependencies thereof were determined in vitro for clarithromycin, fluoxetine, and N-desmethyl diltiazem, which is the primary metabolite of diltiazem. Using the in vitro concentration-dependent rates for loss of activity, in vivo rates of CYP3A4 inactivation were predicted for these compounds at a clinically relevant unbound plasma concentration of 0.1 μM. Based on the predicted rates combined with published rates for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the steady-state concentration of liver CYP3A4 to approximately 72, 39, or 21{\%} of initial levels, respectively. These reductions correspond to 1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the plasma concentration-time curve of a coadministered drug that is eliminated exclusively by hepatic CYP3A4 metabolism. These predicted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primary metabolite of diltiazem, at clinically relevant concentrations, inactivate CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentrations of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated mechanistic inactivation of CYPs play a major role in many clinically observed drug-drug interactions.",
author = "Mayhew, {Bradley S.} and {Jones And}, {David R.} and Hall, {Stephen D.}",
year = "2000",
language = "English",
volume = "28",
pages = "1031--1037",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "9",

}

TY - JOUR

T1 - An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation

AU - Mayhew, Bradley S.

AU - Jones And, David R.

AU - Hall, Stephen D.

PY - 2000

Y1 - 2000

N2 - An in vitro model is proposed to account for the clinically observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic activity resulting from metabolic intermediate complex formation and the concentration dependencies thereof were determined in vitro for clarithromycin, fluoxetine, and N-desmethyl diltiazem, which is the primary metabolite of diltiazem. Using the in vitro concentration-dependent rates for loss of activity, in vivo rates of CYP3A4 inactivation were predicted for these compounds at a clinically relevant unbound plasma concentration of 0.1 μM. Based on the predicted rates combined with published rates for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the steady-state concentration of liver CYP3A4 to approximately 72, 39, or 21% of initial levels, respectively. These reductions correspond to 1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the plasma concentration-time curve of a coadministered drug that is eliminated exclusively by hepatic CYP3A4 metabolism. These predicted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primary metabolite of diltiazem, at clinically relevant concentrations, inactivate CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentrations of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated mechanistic inactivation of CYPs play a major role in many clinically observed drug-drug interactions.

AB - An in vitro model is proposed to account for the clinically observed inhibition of cytochrome P450 (CYP) 3A that results from administration of clarithromycin, fluoxetine, or diltiazem. Rates for loss of CYP3A4 enzymatic activity resulting from metabolic intermediate complex formation and the concentration dependencies thereof were determined in vitro for clarithromycin, fluoxetine, and N-desmethyl diltiazem, which is the primary metabolite of diltiazem. Using the in vitro concentration-dependent rates for loss of activity, in vivo rates of CYP3A4 inactivation were predicted for these compounds at a clinically relevant unbound plasma concentration of 0.1 μM. Based on the predicted rates combined with published rates for in vivo CYP3A degradation, our model predicts that fluoxetine, clarithromycin, and the primary metabolite of diltiazem reduce the steady-state concentration of liver CYP3A4 to approximately 72, 39, or 21% of initial levels, respectively. These reductions correspond to 1.4-, 2.6-, or 4.7-fold increases, respectively, in the area under the plasma concentration-time curve of a coadministered drug that is eliminated exclusively by hepatic CYP3A4 metabolism. These predicted results are in good agreement with reported clinical data. The major implication of this work is that fluoxetine, clarithromycin, and the primary metabolite of diltiazem, at clinically relevant concentrations, inactivate CYP3A4 enzymatic activity at rates sufficient to affect in vivo concentrations of CYP3A4 and thereby affect the clearance of compounds eliminated by this pathway. We speculate that mechanisms involving substrate-mediated mechanistic inactivation of CYPs play a major role in many clinically observed drug-drug interactions.

UR - http://www.scopus.com/inward/record.url?scp=0033831197&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033831197&partnerID=8YFLogxK

M3 - Article

VL - 28

SP - 1031

EP - 1037

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 9

ER -