Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA

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Abstract

Purpose: To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. Methods: In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibitors to CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Studies were also performed with cloned, expressed CYP3A4, CYP2A6, CYP2E1 and CYP2B6 microsomes, and anti-CYP2B6 monoclonal antibody. Results: Known CYP3A4 inhibitors reduced TEPA production. Inhibition with CYP2E1 inhibitors was inconsistent. All other inhibitors produced little or no change in TEPA formation. Cloned, expressed CYP2B6 and CYP3A4 microsomes catalyzed TEPA formation, whereas CYP2A6 and CYP2E1 did not. Incubation of thiotepa with anti-CYP2B6 antibody and cloned, expressed CYP2B6 microsomes resulted in reductions in the formation of TEPA, but no change in TEPA formation occurred in human liver microsomes. Conclusions: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.

Original languageEnglish (US)
Pages (from-to)461-467
Number of pages7
JournalCancer chemotherapy and pharmacology
Volume49
Issue number6
DOIs
StatePublished - Jul 3 2002

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Triethylenephosphoramide
Thiotepa
Cytochrome P-450 CYP3A
Metabolism
Isoenzymes
Microsomes
Cytochrome P-450 CYP2E1
Cytochrome P-450 Enzyme System
Liver Microsomes
Liver
Drug interactions
Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP2D6
Pharmacokinetics
Alkylating Agents
Metabolites
Drug Interactions
Cytochrome P-450 CYP2B6
In Vitro Techniques
Anti-Idiotypic Antibodies

Keywords

  • Cytochrome P450
  • Human microsomes
  • Metabolism
  • TEPA
  • Thiotepa

Cite this

@article{b8265a742b5f4ad98e988076ac01bdd2,
title = "Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA",
abstract = "Purpose: To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. Methods: In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibitors to CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Studies were also performed with cloned, expressed CYP3A4, CYP2A6, CYP2E1 and CYP2B6 microsomes, and anti-CYP2B6 monoclonal antibody. Results: Known CYP3A4 inhibitors reduced TEPA production. Inhibition with CYP2E1 inhibitors was inconsistent. All other inhibitors produced little or no change in TEPA formation. Cloned, expressed CYP2B6 and CYP3A4 microsomes catalyzed TEPA formation, whereas CYP2A6 and CYP2E1 did not. Incubation of thiotepa with anti-CYP2B6 antibody and cloned, expressed CYP2B6 microsomes resulted in reductions in the formation of TEPA, but no change in TEPA formation occurred in human liver microsomes. Conclusions: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.",
keywords = "Cytochrome P450, Human microsomes, Metabolism, TEPA, Thiotepa",
author = "Jacobson, {Pamala A} and K. Green and Birnbaum, {Angela K} and Remmel, {Rory P}",
year = "2002",
month = "7",
day = "3",
doi = "10.1007/s00280-002-0453-3",
language = "English (US)",
volume = "49",
pages = "461--467",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA

AU - Jacobson, Pamala A

AU - Green, K.

AU - Birnbaum, Angela K

AU - Remmel, Rory P

PY - 2002/7/3

Y1 - 2002/7/3

N2 - Purpose: To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. Methods: In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibitors to CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Studies were also performed with cloned, expressed CYP3A4, CYP2A6, CYP2E1 and CYP2B6 microsomes, and anti-CYP2B6 monoclonal antibody. Results: Known CYP3A4 inhibitors reduced TEPA production. Inhibition with CYP2E1 inhibitors was inconsistent. All other inhibitors produced little or no change in TEPA formation. Cloned, expressed CYP2B6 and CYP3A4 microsomes catalyzed TEPA formation, whereas CYP2A6 and CYP2E1 did not. Incubation of thiotepa with anti-CYP2B6 antibody and cloned, expressed CYP2B6 microsomes resulted in reductions in the formation of TEPA, but no change in TEPA formation occurred in human liver microsomes. Conclusions: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.

AB - Purpose: To establish the cytochrome P450 (CYP) isozymes involved in the metabolism of the alkylating agent, thiotepa, to the pharmacologically active metabolite, TEPA. Methods: In vitro chemical inhibition studies were conducted by incubating thiotepa and pooled human hepatic microsomes in the presence of known inhibitors to CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Studies were also performed with cloned, expressed CYP3A4, CYP2A6, CYP2E1 and CYP2B6 microsomes, and anti-CYP2B6 monoclonal antibody. Results: Known CYP3A4 inhibitors reduced TEPA production. Inhibition with CYP2E1 inhibitors was inconsistent. All other inhibitors produced little or no change in TEPA formation. Cloned, expressed CYP2B6 and CYP3A4 microsomes catalyzed TEPA formation, whereas CYP2A6 and CYP2E1 did not. Incubation of thiotepa with anti-CYP2B6 antibody and cloned, expressed CYP2B6 microsomes resulted in reductions in the formation of TEPA, but no change in TEPA formation occurred in human liver microsomes. Conclusions: Thiotepa is metabolized in human liver microsomes by CYP3A4 (major) and CYP2B6 (minor). There is a potential for CYP-mediated drug interactions with thiotepa. Pharmacokinetic variability of thiotepa may be related to expression of hepatic CYP isozymes.

KW - Cytochrome P450

KW - Human microsomes

KW - Metabolism

KW - TEPA

KW - Thiotepa

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U2 - 10.1007/s00280-002-0453-3

DO - 10.1007/s00280-002-0453-3

M3 - Article

C2 - 12107550

AN - SCOPUS:0036090053

VL - 49

SP - 461

EP - 467

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 6

ER -