Stereoselective hepatic disposition of a diastereomeric pair of alphavbeta3 antagonists in rat.
1. The study investigated mechanisms underlying the stereoselective hepatic disposition observed in rats of a zwitterionic diastereomeric pair ((3S)-3-[(3R or 3S)-2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrrolidin-1-yl]-3-quinolin-3-ylpropanoic acid) with different lipophilicities. 2. In a recirculating isolated rat liver system, the more hydrophilic diastereomer II possessed biliary clearance, CLb, and bile-to-liver concentration ratio higher (about 10-30-fold) than the lipophilic zwitterion I, whereas both I and II exhibited comparably high concentration ratios between liver and perfusate. Although MK-571, a known multidrug resistance protein (MRP) inhibitor, significantly inhibited the CLb of both compounds, it did not inhibit their canalicular transport, as evident by unchanged concentration ratios between bile and liver of either I or II. 3. Following an intravenous infusion of I or II to Sprague-Dawley rats, the biliary clearance calculated either based on plasma (CL(b,p)) or liver concentration (CL(b,l)), of II was much higher than that of I (about 5-50-fold). In rats lacking multidrug resistance protein 2 (Mrp2) (Eisai hyperbilirubinemic rat, EHBR), the biliary excretion rate and CL(b,p) of II were also higher than the corresponding values for I. However, both CL(b,p) or CL(b,l) of either I or II were not reduced in EHBR, as compared with control SD rats. 4. In the in vitro rat canalicular membrane vesicle study, I and II exhibited no differences in their inhibitory effect on the Mrp2 mediated ATP-dependent [3H]DNP-SG initial uptake (no inhibition at 10 microM and only about 40% inhibition at 100 microM). 5. Collectively, these results suggested that (1) the difference in the hepatic disposition between the two isomers was due primarily to the difference in their transport mechanism across the canalicular membrane and (2) Mrp2 did not play a major role in the observed differences in the biliary excretion of the diastereomers I and II in rats.
Prueksaritanont
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Department of Drug Metabolism, Merck Reseach Laboratories, West Point, PA 19486, USA. thomayant_prueksaritanont@merck.com
Xu
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Deluna
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Yamazaki
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Lin
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JH
D000818:Animals; D019540:Area Under Curve; D001648:Bile Canaliculi / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006932:Hyperbilirubinemia / Q000378:metabolism; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009287:Naphthyridines; D010477:Perfusion; D011422:Propionates / Q000494:pharmacology*; D011759:Pyrrolidines; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C466950:3-(2-oxo-3-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)pyrrolidin-1-yl)-3-quinolin-3-ylpropanoic acid; D039302:Integrin alphaVbeta3; D009287:Naphthyridines; D011422:Propionates; D011759:Pyrrolidines; D011804:Quinolines; C059141:verlukast