Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers

• Published in: Drug metabolism and pharmacokinetics Vol. 34; no. 1; pp. 78 - 86
• Main Authors: Mori, Daiki, Kashihara, Yushi, Yoshikado, Takashi, Kimura, Miyuki, Hirota, Takeshi, Matsuki, Shunji, Maeda, Kazuya, Irie, Shin, Ieiri, Ichiro, Sugiyama, Yuichi, Kusuhara, Hiroyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2019
• Subjects: Adult; Biomarker; Coproporphyrin I; Endogenous substrate; Female; Gender difference; Genotype; Healthy Volunteers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - blood; Liver-Specific Organic Anion Transporter 1 - blood; Liver-Specific Organic Anion Transporter 1 - genetics; Male; OATP1B1 genotype; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - blood; Statin; Substrate Specificity - physiology; Young Adult; GCDCA-S; Endogenous substrate; Biomarker; CDCA-24G; Coproporphyrin I; Gender difference; DDI; OATP1B3; MRM; Statin; LC–MS/MS; OATP1B1; AUC; CV; CP-I; OCT2; MATE1; TLCA-S; OATP1B1 genotype; LCA-S; GLCA-S
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2018.09.003

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities. [Display omitted]