Premium
Positron Emission Tomography Imaging of [ 11 C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A
Author(s) -
Billington Sarah,
Shoner Steven,
Lee Scott,
ClarkSnustad Kindra,
Pennington Matthew,
Lewis David,
Muzi Mark,
Rene Shirley,
Lee Jean,
Nguyen Tot Bui,
Kumar Vineet,
Ishida Kazuya,
Chen Laigao,
Chu Xiaoyan,
Lai Yurong,
Salphati Laurent,
Hop Cornelis E.C.A.,
Xiao Guangqing,
Liao Mingxiang,
Unadkat Jashvant D.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1506
Subject(s) - efflux , multidrug resistance associated protein 2 , positron emission tomography , rosuvastatin , organic anion transporter 1 , chemistry , bilirubin , organic anion transporting polypeptide , endocrinology , medicine , nuclear medicine , transporter , biochemistry , atp binding cassette transporter , gene
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.