Pre-incubation with cyclosporine A potentiates its inhibitory effects on pitavastatin uptake mediated by recombinantly expressed cynomolgus monkey hepatic organic anion transporting polypeptide.
Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC50) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems. Pre-incubation with cyclosporine A, but not with rifampicin, decreased the apparent IC50values on recombinant cynomolgus monkey OATP1B1- and OATP1B3-mediated pitavastatin uptake. Application of the co-incubated IC50values toward R values (1 + [unbound inhibitor]inlet to the liver, theoretically maximum/inhibition constant) in static models, 1.1 in monkeys and 1.3 in humans, for recombinant cynomolgus monkey and human OATP1B1-mediated pitavastatin uptake might result in the poor prediction of drug interaction magnitudes. In contrast, the lowered IC50values after pre-incubation with cyclosporine A provided better prediction with R values of 3.9 for monkeys and 2.7 for humans when the estimated maximum cyclosporine A concentrations at the inlet to the liver were used. These results suggest that the enhanced inhibitory potential of perpetrator medicines by pre-incubation on cynomolgus monkey OATP-mediated pitavastatin uptake in vitro could be of value for the precise estimation of drug interaction magnitudes in silico, in accordance with the findings from pre-administration of inhibitors on pitavastatin pharmacokinetics validated in monkeys. Copyright © 2016 John Wiley & Sons, Ltd.
Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan. takahashi.tsuyoshi@ma.mt-pharma.co.jp.
Tsuyoshi
T
Takahashi
Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan.
Tatsuyuki
T
Ohtsuka
Shin Nippon Biomedical Laboratories Ltd, Kainan, Wakayama, Japan.
Yasuhiro
Y
Uno
Shin Nippon Biomedical Laboratories Ltd, Kainan, Wakayama, Japan.
Masahiro
M
Utoh
Showa Pharmaceutical University, Machida, Tokyo, Japan.
Hiroshi
H
Yamazaki
Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan.
Toshiyuki
T
Kume
D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000096:biosynthesis*; D008252:Macaca fascicularis; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis*; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D000935:Antifungal Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D011804:Quinolines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016572:Cyclosporine; C108475:pitavastatin
OATP; cyclosporine A; cynomolgus monkeys; inhibitory effect; pre-incubation