title: Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats.
abstract: The new immunosuppressive agent, SDZ-RAD, and its analog rapamycin were examined for intestinal absorption, metabolism, and bioavailability in Wistar rats. Intestinal first-pass metabolism studies from rat jejunum showed that at 0.5 mg of SDZ-RAD/kg rat, 50% of the parent compound was metabolized in the intestinal mucosa, and this decreased to around 30% when SDZ-RAD was increased to 5.0 mg/kg rat. Results for rapamycin at the low dose were similar to those for SDZ-RAD, but at the higher dose only 1 to 14% of the total rapamycin absorbed was metabolized by the intestine. After i.v. administration of 1 mg/kg SDZ-RAD or rapamycin, the area under the concentration curve (AUC) for rapamycin was twice that of SDZ-RAD, resulting in a systemic clearance of 6.2 ml/min and 3.0 ml/min for SDZ-RAD and rapamycin, respectively. However, the AUC for oral absorption was similar for the two compounds: 140 and 172 ng*h/ml for SDZ-RAD and rapamycin, respectively. Because blood clearance was faster for SDZ-RAD after i.v. administration, the absolute oral bioavailability for SDZ-RAD was 16% compared with 10% for rapamycin. Overall, the data suggest that intestinal first pass is a major site of metabolism for SDZ-RAD and rapamycin and that intestinal absorption of SDZ-RAD was much faster than that of rapamycin. This allowed it to counteract the combined actions of faster systemic clearance and increased intestinal metabolism, resulting in comparable absolute exposure when given orally. Also, the coadministration of cyclosporin A with SDZ-RAD was shown to dramatically increase blood AUCs for SDZ-RAD, probably through saturating intestinal metabolism mechanisms.
authors.affiliation: Compound Formulation and Selection Support/Drug Metabolism and Pharmacokinetics, Novartis Pharma Inc., Basel, Switzerland. andrew.crowe@pharma.novartis.com
authors.forename: A
authors.initials: A
authors.lastname: Crowe
authors.forename: A
authors.initials: A
authors.lastname: Bruelisauer
authors.forename: L
authors.initials: L
authors.lastname: Duerr
authors.forename: P
authors.initials: P
authors.lastname: Guntz
authors.forename: M
authors.initials: M
authors.lastname: Lemaire
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus