title: Comparison of intestinal metabolism of CYP3A substrates between rats and humans: application of portal-systemic concentration difference method.
abstract: 1. Rats are frequently used in pharmacokinetic studies during drug discovery. However, there is limited information regarding species differences in intestinal availability (Fg) between rats and humans. 2. Here, we directly estimated the fraction of dose absorbed in the portal vein (FaFg) of rats for nine CYP3A substrates using portal-systemic concentration difference method and compared them with human FaFg. No distinct difference in FaFg between the two species was observed, and seven of the nine compounds were within a two-fold difference. Given that their net fraction of dose absorbed (Fa) are expected to be high, this result indicates a moderate correlation in Fg between the two species. 3. In contrast, the in vitro intrinsic clearance (CLint,u) in rat intestinal microsomes tended to be lower than that in humans, and the correlation between intestinal CLint,u and FaFg in rats was poor compared with that in humans. 4. Our finding indicates that rats are appropriate animals for evaluation of the intestinal absorption and metabolism of CYP3A substrates. However, a degree of caution is required when estimating rat Fg from rat intestinal microsomes due to the low metabolic activity and the poor correlation between in vitro and in vivo intestinal metabolism.
authors: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc. , Ibaraki , Japan.
authors: Keitaro
authors: K
authors: Kadono
authors: Akiko
authors: A
authors: Koakutsu
authors: Yoichi
authors: Y
authors: Naritomi
authors: Shigeyuki
authors: S
authors: Terashita
authors: Kenji
authors: K
authors: Tabata
authors: Toshio
authors: T
authors: Teramura
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods*; D002417:Cattle; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011168:Portal System / Q000378:metabolism*; D011169:Portal Vein / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors; D015262:Xenobiotics / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D015262:Xenobiotics; D012710:Serum Albumin, Bovine; D051544:Cytochrome P-450 CYP3A