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Positron Emission Tomography Imaging of [11 C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A.

Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals (Europe) Ltd., Abingdon-on-Thames, UK. Department of Radiology, University of Washington, Seattle, Washington, USA. Inflammatory Bowel Disease Program, University of Washington, Seattle, Washington, USA. Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, Washington, USA. Pharmacokinetics and Drug Metabolism, Amgen, Cambridge, Massachusetts, USA. Early Clinical Development, Worldwide Research and Development, Pfizer Inc., Cambridge, Massachusetts, USA. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey, USA. Department of Drug Metabolism, Gilead Sciences, Inc., Foster City, California, USA. Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA. Drug Metabolism and Pharmacokinetics, Biogen, Cambridge, Massachusetts, USA. Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA.

Clinical pharmacology and therapeutics. 2019;(5):1056-1066
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Abstract

Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11 C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11 C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic-anion-transporting polypeptide, Na+ -taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11 C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.

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Publication Type : Clinical Trial

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