Mechanism-based inactivation of CYP2C19 and CYP2D6 by tamoxifen (TAM) and its metabolite n-desmethyltamoxifen (NDTAM)

Zeruesenay Desta, J. Park, N. Soukhova, D. A. Flockhart

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Abstract

We tested the inhibitory effect of tamoxifen (TAM) and its metabolite NDTAM on the activities of human CYP 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 in human liver microsomes (HLMs), using isoform-specific substrate probes. TAM and NDTAM showed potent inhibition of 2C19 and 2D6, with negligible effect on other isoforms. Since TAM and NDTAM have structural features that can form intermediate complexes with CYP450s, we preincubated (0-30min) them in HLMs and NADPH before initiating the reaction with substrate probes and noted further decreases of CYP2C19 and CYP2D6 activities in a time and concentration dependent manner. In the table, the rate of inactivation (Kinact) and the inhibitor concentration that produced half-maximum inactivation (K'i) are shown. Apparent inhibition constants (Ki values) of TAM with the 30min preincubation were 2.9±0.2μM for 2C19 and 6.8±1.3μM for 2D6. TAM NDTAM P450s Kinact(min-1) K'i(μM) Kinact(min-1) K'i(μM) 2C19 0.06 2.4 0.04 11.5 2D6 0.02 4.3 0.017 5.4 TAM may decrease the clearance of coadministered 2C19 and 2D6 substrate drugs via mechanism-based inhibition.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001
Externally publishedYes

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Cytochrome P-450 CYP2D6
Tamoxifen
Liver Microsomes
Protein Isoforms
Cytochrome P-450 CYP1A2
NADP
Human Activities
Cytochrome P-450 CYP2C19
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

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Mechanism-based inactivation of CYP2C19 and CYP2D6 by tamoxifen (TAM) and its metabolite n-desmethyltamoxifen (NDTAM). / Desta, Zeruesenay; Park, J.; Soukhova, N.; Flockhart, D. A.

In: Clinical Pharmacology and Therapeutics, Vol. 69, No. 2, 2001.

Research output: Contribution to journalArticle

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abstract = "We tested the inhibitory effect of tamoxifen (TAM) and its metabolite NDTAM on the activities of human CYP 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 in human liver microsomes (HLMs), using isoform-specific substrate probes. TAM and NDTAM showed potent inhibition of 2C19 and 2D6, with negligible effect on other isoforms. Since TAM and NDTAM have structural features that can form intermediate complexes with CYP450s, we preincubated (0-30min) them in HLMs and NADPH before initiating the reaction with substrate probes and noted further decreases of CYP2C19 and CYP2D6 activities in a time and concentration dependent manner. In the table, the rate of inactivation (Kinact) and the inhibitor concentration that produced half-maximum inactivation (K'i) are shown. Apparent inhibition constants (Ki values) of TAM with the 30min preincubation were 2.9±0.2μM for 2C19 and 6.8±1.3μM for 2D6. TAM NDTAM P450s Kinact(min-1) K'i(μM) Kinact(min-1) K'i(μM) 2C19 0.06 2.4 0.04 11.5 2D6 0.02 4.3 0.017 5.4 TAM may decrease the clearance of coadministered 2C19 and 2D6 substrate drugs via mechanism-based inhibition.",
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T1 - Mechanism-based inactivation of CYP2C19 and CYP2D6 by tamoxifen (TAM) and its metabolite n-desmethyltamoxifen (NDTAM)

AU - Desta, Zeruesenay

AU - Park, J.

AU - Soukhova, N.

AU - Flockhart, D. A.

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Y1 - 2001

N2 - We tested the inhibitory effect of tamoxifen (TAM) and its metabolite NDTAM on the activities of human CYP 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 in human liver microsomes (HLMs), using isoform-specific substrate probes. TAM and NDTAM showed potent inhibition of 2C19 and 2D6, with negligible effect on other isoforms. Since TAM and NDTAM have structural features that can form intermediate complexes with CYP450s, we preincubated (0-30min) them in HLMs and NADPH before initiating the reaction with substrate probes and noted further decreases of CYP2C19 and CYP2D6 activities in a time and concentration dependent manner. In the table, the rate of inactivation (Kinact) and the inhibitor concentration that produced half-maximum inactivation (K'i) are shown. Apparent inhibition constants (Ki values) of TAM with the 30min preincubation were 2.9±0.2μM for 2C19 and 6.8±1.3μM for 2D6. TAM NDTAM P450s Kinact(min-1) K'i(μM) Kinact(min-1) K'i(μM) 2C19 0.06 2.4 0.04 11.5 2D6 0.02 4.3 0.017 5.4 TAM may decrease the clearance of coadministered 2C19 and 2D6 substrate drugs via mechanism-based inhibition.

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