PET Imaging of Oatp-Mediated Hepatobiliary Transport of [11C] Rosuvastatin in the Rat

被引:43
作者
He, Jiake [1 ,2 ]
Yu, Yang [1 ]
Prasad, Bhagwat [1 ]
Link, Jeanne [3 ]
Miyaoka, Robert S. [3 ]
Chen, Xijing [2 ]
Unadkat, Jashvant D. [1 ]
机构
[1] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA
[2] China Pharmaceut Univ, Ctr Drug Metab & Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China
[3] Univ Washington, Dept Radiol, Seattle, WA 98195 USA
关键词
C-11]-rosuvastatin; PET; hepatobiliary transport; rat; RESISTANCE-ASSOCIATED PROTEIN-2; SANDWICH-CULTURED HEPATOCYTES; POSITRON-EMISSION-TOMOGRAPHY; ORGANIC ANION TRANSPORTER; A REDUCTASE INHIBITOR; ADULT MALE-VOLUNTEERS; MULTIPLE TRANSPORTERS; HEPATIC-UPTAKE; IN-VITRO; PHARMACOKINETICS;
D O I
10.1021/mp500027c
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
A novel positron emission tomography (PET) tracer, [C-11]-rosuvastatin (RSV), was developed to dynamically and non-invasively measure hepatobiliary transport and tissue distribution of [C-11]-RSV in rats. Methods: Male Sprague Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [C-11]-rosuvastatin (similar to 1 mCi/30 s, iv infusion). After [C-11]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five-compartment model) analysis. Results: The majority of the [C-11]-RSV dose was distributed into the liver. In the presence of RIP, the area under the [C-11]-RSV radioactivity blood concentration time profile (AUC(0-90min),;) was increased by similar to 3-fold. Relative to the control animals, RIF reduced the distribution of [C-11]-RSV radioactivity into the liver and kidney (tissue AUC(0-15min) min/bloo(1 AUC(0-15min)) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. Conclusion: [C-11] -RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans.
引用
收藏
页码:2745 / 2754
页数:10
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