Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants

Takeshi Akiyoshi, Marie Ito, Saori Murase, Mitsue Miyazaki, F. Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Hisakazu Ohtani

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.

Original languageEnglish
Pages (from-to)411-415
Number of pages5
JournalDrug Metabolism and Pharmacokinetics
Volume28
Issue number5
DOIs
Publication statusPublished - 2013

Fingerprint

Cytochrome P-450 CYP3A
Clarithromycin
Erythromycin
Drug Interactions
Pharmaceutical Preparations
Hydroxylation
Testosterone

Keywords

  • Clarithromycin
  • CYP3A4
  • Erythromycin
  • Genetic variants
  • Mechanism-based inhibition

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Pharmaceutical Science

Cite this

Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. / Akiyoshi, Takeshi; Ito, Marie; Murase, Saori; Miyazaki, Mitsue; Peter Guengerich, F.; Nakamura, Katsunori; Yamamoto, Koujirou; Ohtani, Hisakazu.

In: Drug Metabolism and Pharmacokinetics, Vol. 28, No. 5, 2013, p. 411-415.

Research output: Contribution to journalArticle

Akiyoshi, Takeshi ; Ito, Marie ; Murase, Saori ; Miyazaki, Mitsue ; Peter Guengerich, F. ; Nakamura, Katsunori ; Yamamoto, Koujirou ; Ohtani, Hisakazu. / Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. In: Drug Metabolism and Pharmacokinetics. 2013 ; Vol. 28, No. 5. pp. 411-415.
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abstract = "Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.",
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AU - Peter Guengerich, F.

AU - Nakamura, Katsunori

AU - Yamamoto, Koujirou

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AB - Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.

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