Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Abstract

where Fa is the fraction of dose absorbed from the gastrointestinal (GI) tract, Fg is the intestinal availability, that correspondent to the fraction of dose not metabolized in the intestinal wall during the absorption process and Fh is the fraction of dose not metabolized in the liver before reaching the systemic circulation. Therefore, the values of (1ϪFg) and (1ϪFh) mean the first-pass metabolism of orally administered drugs in GI tract and the liver, respectively. In order to select the appropriate candidates for oral drug product, quantitative assessments on each process are highly required.Recently, not only the small animals such as mice and rats, but also cynomolgus monkeys are often used as an animal model for PK studies in the drug discovery stage. However, lower oral BAs of test compounds were often observed in cynomolgus monkeys compared with those in other animals.1,2) Also in our previous study, various marketed drugs showed low oral BAs in cynomolgus monkeys than those in humans. From the kinetic analysis of the plasma concentrations of drugs after intravenous and oral administration, it was indicated that the low oral BAs in cynomolgus monkeys are mostly attributed to the low value of Fa*Fg.3,4) However, only from the in vivo PK analysis, it is theoretically impossible to evaluate Fa and Fg separately, resulting the confusion in the contribution of intestinal absorption on the oral BA of various drugs.Tamura et al. investigated the mechanisms of intestinal absorption of tacrolims by using the simultaneous perfusion method of intestinal lumen and mesenteric veins in rats. 5)They have calculated the fraction of metabolized in the intestinal cells from the difference between eliminated amount of the drug from the intestinal lumen and absorbed amount into the blood perfusate. Also, Mihara et al. evaluated quantitatively the first-pass metabolism of eperison in rats by using the similar perfusion method. 6) Although the simultaneous perfusion method is useful to assess the intestinal metabolism of drugs, this method requires complicated operations of the mesenteric vein and is difficult to perform in cynomolgus monkeys. Moreover, perfusion of the mesenteric vein might affect the absorption and metabolism of drugs in the intestine.The present study is performed 1) to establish the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys and then 2) to clarify the causes of low BA of drugs in cynomolgus monkeys. For these purposes, an in situ single-pass intestinal perfusion method was performed with blood sampling from both portal and peripheral veins, instead of the perfusion of the mesenteric vein. The intestinal permeability of drugs (P eff ) is calculated from the decrease in drug concentration in the perfusate after single pass perfusion through the intestinal tract. The intestinal metabolism during the absorption process (1ϪFg) is calculated from the difference between drug amounts that disappeared from the perfusate and absorbed into the por...

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