Clinical evaluation of [18F]pitavastatin for quantitative analysis of hepatobiliary transporter activity

Takayoshi Nakaoka; Ken-Ichi Kaneko; Satsuki Irie; Aya Mawatari; Ami Igesaka; Yuta Uetake; Hidenori Ochiai; Takashi Niwa; Emi Yamano; Yasuhiro Wada; Masaaki Tanaka; Kohei Kotani; Hideki Kawahata; Joji Kawabe; Yukio Miki; Hisashi Doi; Takamitsu Hosoya; Maeda Kazuya; Hiroyuki Kusuhara; Yuichi Sugiyama; Yasuyoshi Watanabe

doi:10.1016/j.dmpk.2022.100449

Clinical evaluation of [¹⁸F]pitavastatin for quantitative analysis of hepatobiliary transporter activity

Drug Metab Pharmacokinet. 2022 Jun:44:100449. doi: 10.1016/j.dmpk.2022.100449. Epub 2022 Feb 1.

Authors

Takayoshi Nakaoka¹, Ken-Ichi Kaneko¹, Satsuki Irie¹, Aya Mawatari¹, Ami Igesaka², Yuta Uetake², Hidenori Ochiai², Takashi Niwa¹, Emi Yamano³, Yasuhiro Wada¹, Masaaki Tanaka⁴, Kohei Kotani⁵, Hideki Kawahata⁶, Joji Kawabe⁷, Yukio Miki⁸, Hisashi Doi¹, Takamitsu Hosoya⁹, Maeda Kazuya¹⁰, Hiroyuki Kusuhara¹¹, Yuichi Sugiyama¹², Yasuyoshi Watanabe¹³

Affiliations

¹ RIKEN Center for Life Science Technologies CLST, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; RIKEN Center for Biosystems Dynamics Research BDR, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
² RIKEN Center for Life Science Technologies CLST, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
³ RIKEN Center for Biosystems Dynamics Research BDR, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
⁴ Department of Physiology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, 545-8585, Japan.
⁵ Department of Hepatology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, 545-8585, Japan.
⁶ Department of Radiology, Osaka City University Hospital, Abeno-ku, Osaka, 545-8586, Japan.
⁷ Department of Nuclear Medicine, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, 545-8585, Japan.
⁸ Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, 545-8585, Japan.
⁹ RIKEN Center for Life Science Technologies CLST, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; RIKEN Center for Biosystems Dynamics Research BDR, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University TMDU, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan.
¹⁰ Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan; Kitasato University School of Pharmacy, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
¹¹ Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
¹² Sugiyama Laboratory, RIKEN Innovation Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan; Laboratory of Quantitative System Pharmacokinetics / Pharmacodynamics, School of Pharmacy, Josai International University, Kioi-cho, Tokyo, 102-0093, Japan.
¹³ RIKEN Center for Life Science Technologies CLST, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; RIKEN Center for Biosystems Dynamics Research BDR, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. Electronic address: yywata@riken.jp.

PMID: 35395593
DOI: 10.1016/j.dmpk.2022.100449

Abstract

It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([¹⁸F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [¹⁸F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [¹⁸F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans.

Keywords: (18)F]pitavastatin; Canalicular efflux clearance; Drug-drug interaction; Hepatic uptake clearance; Hepatobiliary transporter activity; Positron emission tomography; Rifampicin.

MeSH terms

Biological Transport
Humans
Liver / metabolism
Membrane Transport Proteins / metabolism
Quinolines* / metabolism
Quinolines* / pharmacology
Rifampin* / metabolism
Rifampin* / pharmacology

Substances

Membrane Transport Proteins
Quinolines
pitavastatin
Rifampin