Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats

Tetsuya Aiba, Yutaka Takehara, Marie Okuno, Yukiya Hashimoto

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose. To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats. Methods. The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis. Results. Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrata desipramine, not by a CYP3A4 inhibitor ketoconazole, In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver. Conclusions. Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.

Original languageEnglish
Pages (from-to)745-748
Number of pages4
JournalPharmaceutical Research
Volume20
Issue number5
DOIs
Publication statusPublished - May 1 2003
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Metabolism
Rats
Rifabutin
Lidocaine
Liver
Substrates
Liver Microsomes
Intestines
Tissue
Cytochrome P-450 CYP2D6
Desipramine
Quinidine
Ketoconazole
Pharmaceutical Preparations
Biological Availability
Western Blotting

Keywords

  • CYP3A1
  • CYP3A2
  • CYP3A4
  • Intestinal metabolism
  • Substrate specificity

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats. / Aiba, Tetsuya; Takehara, Yutaka; Okuno, Marie; Hashimoto, Yukiya.

In: Pharmaceutical Research, Vol. 20, No. 5, 01.05.2003, p. 745-748.

Research output: Contribution to journalArticle

Aiba, Tetsuya ; Takehara, Yutaka ; Okuno, Marie ; Hashimoto, Yukiya. / Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats. In: Pharmaceutical Research. 2003 ; Vol. 20, No. 5. pp. 745-748.
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