Evaluation of rosuvastatin as an organic anion transporting polypeptide (OATP) probe substrate: in vitro transport and in vivo disposition in cynomolgus monkeys.
Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug-drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro-in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [(3)H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0-inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition.
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.) hong.shen1@bms.com.
Hong
H
Shen
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Hong
H
Su
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Tongtong
T
Liu
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Ming
M
Yao
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Gabe
G
Mintier
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Lun
L
Li
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
R Marcus
RM
Fancher
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Ramaswamy
R
Iyer
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Punit
P
Marathe
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
Yurong
Y
Lai
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People's Republic of China (L.L.).
A David
AD
Rodrigues
D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D005464:Fluorobenzenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D057809:HEK293 Cells; D006801:Humans; D007553:Isotope Labeling; D008252:Macaca fascicularis; D008297:Male; D015335:Molecular Probes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D027361:Organic Anion Transporters / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000068718:Rosuvastatin Calcium; D013045:Species Specificity; D013449:Sulfonamides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D027981:Symporters / Q000378:metabolism
D005464:Fluorobenzenes; D015335:Molecular Probes; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D011743:Pyrimidines; D013449:Sulfonamides; D027981:Symporters; C071908:sodium-bile acid cotransporter; D016572:Cyclosporine; D000068718:Rosuvastatin Calcium