In vitro–in vivo extrapolation of CYP2C8-catalyzed paclitaxel 6α-hydroxylation: effects of albumin on in vitro kinetic parameters and assessment of interindividual variability in predicted clearance

Abstract

Human liver microsomal K(m) and intrinsic clearance values are over- and underpredicted, respectively, when incubations of the CYP2C8 substrate paclitaxel are performed without BSA supplementation. IV-IVE based on kinetic parameters generated in the presence of BSA improves the accuracy of predicted paclitaxel hepatic clearance.

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

“…Overprediction of drug-drug interactions has been reported for CYP3A4 inactivation by various kinase inhibitors (Kenny et al, 2012). For experimentally determined kinetic parameters (such as K i ), nonspecific binding and albumin tend to decrease "effective concentrations" of some drugs and lead to overestimation of parameters obtained from HLM incubations (Margolis and Obach 2003;Wattanachai et al, 2011;Nagar and Korzekwa 2012). The decreased inhibitory potency due to overestimation of K i values may result in underprediction of drug-drug interaction potential, a phenomenon was not seen during our analysis.…”

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

“…Because enhancement of the activities of several P450 and UGT enzymes by BSA apparently arises from sequestration of inhibitory fatty acids, including arachidonic, linoleic, oleic, or other long-chain unsaturated fatty acids depending on the enzyme source (Rowland et al, 2007(Rowland et al, , 2008aWattanachai et al, 2011), the present study investigated the effects of BSA on the high-affinity components of human liver microsomal PHEN and LID deethylation, and rCYP1A2 catalyzed PHEN Odeethylation and LID N-deethylation. Supplementation of incubations of HLM with BSA (2%, w/v) resulted in an approximate 70% reduction in the mean K m values for the high-affinity components of PHEN and LID deethylation without an effect on V max .…”

“…Addition of the individual proteins to incubations of human liver microsomes (HLM) or recombinant enzyme enhances activity, primarily via a decrease in K m and hence an increase in the in vitro intrinsic clearance (CL int ). Increased activity in the presence of BSA (2% w/v), fatty acid-free human serum albumin (2% w/v), and/or intestinal fatty acid binding protein (1% w/v) has been demonstrated for CYP2C8 (Wattanachai et al, 2011), CYP2C9 (Tang et al, 2002;Rowland et al, 2008a;Kilford et al, 2009), UGT1A9 (Rowland et al, 2008b), UGT2B4 (Raungrut et al, 2010), and UGT2B7 (Rowland et al, 2007(Rowland et al, , 2009; Kilford et al, 2009). Furthermore, the K i values of inhibitors of UGT2B4 and UGT2B7 are reduced when incubations are supplemented with BSA (Rowland et al, 2006;Uchaipichat et al, 2006;Raungrut et al, 2010).…”

“…The "albumin effect" appears to arise from sequestration of long-chain polyunsaturated fatty acids released from membranes during the course of an incubation. In particular, it has been demonstrated that arachidonic acid, linoleic acid, and oleic acid are potent inhibitors of human liver (or kidney) microsomal and recombinant CYP2C8, CYP2C9, UGT1A9, and UGT2B7 (Yamazaki and Shimada, 1999;Tsoutsikos et al, 2004;Yao et al, 2006;Rowland et al, 2007Rowland et al, , 2008aRowland et al, , 2009Wattanachai et al, 2011).…”

Using Simcyp to project human oral pharmacokinetic variability in early drug research to mitigate mechanism‐based adverse events

“…However, due to the evolving nature of this nascent technology and the complexities associated with projecting human plasma drug concentration-time curves (let alone human pharmacokinetic parameters), the majority of published PBPK work has used already amassed human pharmacokinetic data to either test the predictive value of certain models [19,20] or, in combination with human in vitro drug metabolism data, to anticipate future clinical pharmacokinetics. The latter is best exemplified by using PBPK models to conduct drug-drug interaction simulations [21][22][23][24][25], to assess bioavailability [26,27], to simulate exposure parameters in particular populations [28][29][30] and to forecast interindividual pharmacokinetic variability [31,32]. For the situation described here, in which it was desired during lead development to estimate the sufficiency of separation between the C max of an expected clinically efficacious oral dose and a primary pharmacology-based AE threshold (C AE ), PBPK modeling was undertaken at an uncharacteristically earlier stage of the drug life cycle to aid in compound selection for preliminary large animal toxicology studies.…”