Characterization of Long-Lasting Oatp Inhibition by Typical Inhibitor Cyclosporine A and In Vitro-In Vivo Discrepancy in Its Drug Interaction Potential in Rats.
Quantitative assessment of potential drug-drug interactions (DDIs) is one of the major focuses in drug development. The aim of the present study was to quantitatively evaluate in vitro-in vivo discrepancy of DDI potential for prototypical organic anion transporting polypeptide (Oatp) inhibitor cyclosporine A (CsA) using rats. Plasma concentration of pravastatin, prototypical Oatp substrate, after oral administration was increased by CsA intravenously administered at 1 d before the pravastatin administration. The ratio of the area under the curve of pravastatin to the control was much higher than the R-values calculated using the plasma unbound concentrations of CsA and the inhibition constant (Ki) assessed in isolated hepatocytes, indicating in vitro-in vivo discrepancy. This interaction with pravastatin persisted for 3 d after CsA administration, demonstrating long-lasting inhibition in vivo. The Ki value for unbound CsA in the presence of serum was comparable with that in its absence. M1, the major metabolite of CsA inhibited pravastatin uptake at much higher concentration compared with its plasma unbound concentration. Thus, the DDI potential of CsA-mediated hepatic Oatp inhibition cannot be extrapolated from in vitro data, and this could be due to the long-lasting Oatp inhibition by CsA, but not the effect of plasma protein or metabolites.
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Takayuki
T
Taguchi
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Yusuke
Y
Masuo
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Tatsuya
T
Kogi
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Noritaka
N
Nakamichi
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: ykato@p.kanazawa-u.ac.jp.
Yukio
Y
Kato
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D017035:Pravastatin / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D018435:ATP Binding Cassette Transporter, Subfamily B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D016572:Cyclosporine; D017035:Pravastatin; D008874:Midazolam
CYP enzymes; drug interactions; hepatocytes; in vitro/in vivo correlations; multidrug resistance transporters; organic anion-transporting polypeptide transporters; pharmacokinetics; protein binding; solute transporters; transporters