TY - JOUR
T1 - Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats
AU - Aiba, Tetsuya
AU - Takehara, Yutaka
AU - Okuno, Marie
AU - Hashimoto, Yukiya
N1 - Funding Information:
We thank Dr. Tsutomu Sakuma and Dr. Nobuo Nemoto for valuable discussion on analytical techniques. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
KW - CYP3A1
KW - CYP3A2
KW - CYP3A4
KW - Intestinal metabolism
KW - Substrate specificity
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U2 - 10.1023/A:1023429401738
DO - 10.1023/A:1023429401738
M3 - Article
C2 - 12751629
AN - SCOPUS:0037406440
VL - 20
SP - 745
EP - 748
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 5
ER -