Cutting edge Seminar
Speaker: Seiji Miyauchi （Professor, Faculty of Pharmaceutical Sciences and Frontier Biosciences, Toho University）
Title: Efficient uptakes of highly bound drugs by the liver: In vitro and in vivo extrapolation of hepatic uptake clearances for drugs with high protein binding by accounting for the “albumin mediated” hepatic uptake mechanism
Date&Time: 30 Jan. (Wed.) 2019, 12:00- 13:00
Venue: Conference Room(1F), IMEG
Abstract:
It is very important that the pharmacokinetic features of new chemical entities in humans are adequately predicted during early stages of drug discovery and development. In particular, the prediction of human hepatic clearance is crucial because the liver is the major organ responsible for elimination of a variety of endogenous and exogenous chemicals via efficient uptake, metabolism and/or biliary excretion. To date, human liver specimens such as suspended hepatocytes are available for in vitro studies, greatly improving the quantitative in vitro-to-in vivo extrapolation (IVIVE) for hepatic clearance values. On the other hand, compared with anion drugs, anionic drugs with high plasma binding tend to have poor predictive accuracy for human hepatic clearances because they require mechanistic elucidation and quantitative improvement.
Recently, we demonstrated that organic anion transporting polypeptide (OATP) substrates were taken up by human suspended hepatocytes in the presence of albumin, to a much greater extent than could be expected on the basis of the “free drug” hypothesis (Fukuchi et al., 2017; Miyauchi et al., 2018). The enhancement of the hepatic uptake (often referred to as “albumin-mediated” hepatic uptake) has been described in the “facilitated-dissociation” model, in which the drug–albumin complex interacts with the cell surface, enhancing the dissociation of the complex and providing unbound drug for hepatic uptake. It is possible that the “albumin-mediated” hepatic uptake mechanism is responsible for these poor predictions by IVIVE. Furthermore, we also demonstrated using suspended human hepatocytes that the prediction of the uptake clearances of 11anionic drugs known as OATP substrates are improved in accuracy by consideration of the “albumin-mediated” hepatic uptake mechanism (Kim et al., 2019). Together, these results provide solid evidence supporting a kinetic model for describing the “albumin-mediated” hepatic uptake phenomenon for a drug with avidly bound to albumin, which is important for robust IVIVE. In this presentation, I will present not only a clinical importance of the “albumin-mediated” hepatic uptake mechanism, but also the physiological relevance.
Reference:
Fukuchi Y, Toshimoto K, Mori T, Kakimoto K, Tobe Y, Sawada T, Asaumi R, Iwata T, Hashimoto Y, Nunoya KI, Imawaka H, Miyauchi S, and Sugiyam Y (2017) Analysis of Nonlinear Pharmacokinetics of a Highly Albumin-Bound Compound: Contribution of Albumin-Mediated Hepatic Uptake Mechanism. J Pharm Sci 106:2704-2714.
Kim SJ, Lee KR, Miyauchi S, and Sugiyama Y (2019) Extrapolation of In Vivo Hepatic Clearance from In Vitro Uptake Clearance by Suspended Human Hepatocytes for Anionic Drugs with High Binding to Human Albumin: Improvement of In Vitro-to-In Vivo Extrapolation by Considering the “Albumin-Mediated” Hepatic Uptake Mechanism on the Basis of the “Facilitated-Dissociation Model”. Drug Metab Dispos 47:94-103.
Miyauchi S, Masuda M, Kim SJ, Tanaka Y, Lee KR, Iwakado S, Nemoto M, Sasaki S, Shimono K, Tanaka Y, and Sugiyama Y (2018) The Phenomenon of Albumin-Mediated Hepatic Uptake of Organic Anion Transport Polypeptide Substrates: Prediction of the In Vivo Uptake Clearance from the In Vitro Uptake by Isolated Hepatocytes Using a Facilitated-Dissociation Model. Drug Metab Dispos 46:259-267.
