Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats.
OBJECTIVE
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 substrate 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.
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Tetsuya
T
Aiba
Yutaka
Y
Takehara
Marie
M
Okuno
Yukiya
Y
Hashimoto
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D007422:Intestines / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human