Contribution of rat intestinal metabolism to the xenobiotics clearance.
Michaelis-Menten constants K m and V max values were determined by product formation and substrate depletion at several substrate concentrations of 4-methylumbelliferone using rat intestinal microsomes. K m and V max values determined by measuring product formation were in good agreement with substrate depletion approach. We also investigated hepatic and intestinal in vitro intrinsic clearance (CLint) in the liver and intestinal microsomes and compare with reports in the literature using nine test compounds, atorvastatin, 7-ethoxycoumarin, indomethacin, 4-methylumbelliferone, midazolam, nifedipine, testosterone, terfenadine and verapamil, in rats. CLint was determined from the substrate disappearance rate at 0.1 and 0.5 μM in the rat intestinal and liver microsomes, respectively. These results showed that both the liver and the intestine contributed to the metabolism of these compounds. The intestinal intrinsic clearance values of all these drugs, except for terfenadine in the rat intestinal microsomes, were lower than their hepatic intrinsic clearance per milligram protein, showing that there was an organ difference in metabolism between the liver and intestinal. These results make the evaluation using the intestinal more useful and provide a basis for predicting clearance using intestinal.
Bioanalytics, Metabolism and in vitro Technologies, DMPK, Aptuit, Via A. Fleming, 4, 37135, Verona, Italy. mahmud.kajbaf@aptuit.com
Mahmud
M
Kajbaf
Raffaella
R
Ricci
Serenella
S
Zambon
Stefano
S
Fontana
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D015262:Xenobiotics / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
D015262:Xenobiotics