In Vitro to In Vivo Extrapolation of Metabolic Clearance for UGT Substrates Using Short-Term Suspension and Long-Term Co
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Research Article In Vitro to In Vivo Extrapolation of Metabolic Clearance for UGT Substrates Using Short-Term Suspension and Long-Term Co-cultured Human Hepatocytes Luca Docci,1,2 Florian Klammers,1 Aynur Ekiciler,1 Birgit Molitor,1 Kenichi Umehara,1 Isabelle Walter,1 Stephan Krähenbühl,2 Neil Parrott,1 and Stephen Fowler1,3
Received 25 May 2020; accepted 10 July 2020 Abstract.
The use of micro-patterned co-cultured hepatocytes for human hepatic clearance predictions has previously been demonstrated using drugs metabolized by cytochrome P450 enzymes. The present study evaluates the in vitro to in vivo extrapolation (IVIVE) performance for UDP-glucuronosyltransferase (UGT) substrates. In vitro intrinsic clearances for 13 drugs mainly cleared by UGTs were determined using HepatoPac and suspended hepatocytes. The in vivo intrinsic clearance was predicted from in vitro intrinsic clearance and compared with weighted mean in vivo intrinsic clearance estimated from several clinical studies. A conventional scaling methodology accounting for protein binding in plasma and incubation medium was used for the IVIVE assuming that only free drug is accessible at the site of metabolism. The in vivo hepatic intrinsic clearance was predicted within threefold error for six and nine out of thirteen drugs using suspended hepatocytes and HepatoPac, respectively. A reduced under-estimation of hepatic intrinsic clearance was observed in the average fold error (AFE) in HepatoPac (AFE, 0.69) compared with the suspended hepatocytes (AFE, 0.37). The current study shows reasonable performance of hepatic clearance prediction of drugs mainly metabolized by UGT enzymes using HepatoPac with a similar under-prediction bias as obtained in the reported IVIVEs for cytochrome P450 substrates. This study provides a validation of the approach for drugs cleared via UGT conjugation mechanisms and discusses potential causes for outlier behavior considering pharmacokinetic or physicochemical properties. KEY WORDS: UGT; Drug metabolism; In vitro; IVIVE; Hepatocytes.
INTRODUCTION The optimization of metabolic stability in vitro in early drug discovery is important to enable selection of candidate drugs which may be administered daily in acceptable drug quantities. The original online version of the article was revised: During production, the figure captions for Figure 1 and Figure 2 were inadvertently switched in the proofing stage. Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-020-00482-9) contains supplementary material, which is available to authorized users. 1
Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, 4070, Basel, Switzerland. 2 Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland. 3 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: IVIVE, In vitro to in vivo extrapolation; UGT, UDPglucuronosyltransferase; CYP, Cytochrome P450; CLint, Intrinsic clearance; CLp
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