Commentary: Nonspecific Protein Binding versus Membrane Partitioning: It Is Not Just Semantics

Nagar, Swati; Korzekwa, Kenneth R.

doi:10.1124/dmd.112.046599

Cited by 60 publications

(51 citation statements)

References 30 publications

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“…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.…”

Section: Discussionmentioning

confidence: 70%

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

Wang

Pan

et al. 2014

Drug Metab Dispos

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Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K i values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathwaydependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K I of 0.93 mM and k inact of 0.0137 min 21 , and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate (s). Using a static model, a reasonably accurate prediction of drug-drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.

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Section: Discussionmentioning

confidence: 70%

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

Wang

Pan

et al. 2014

Drug Metab Dispos

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“…Besides the mentioned processes, membrane partitioning, nonspecific protein binding, and biotransformation dominantly contribute to drug disposition in a cell (Anzenbacher and Anzenbacherova, 2001;Guengerich, 2006;Balaz, 2009;Seddon et al, 2009;Lucio et al, 2010;Endo et al, 2011;Nagar and Korzekwa, 2012). In humans, most marketed drugs undergo biotransformation processes catalyzed by P450 enzymes (Evans and Relling, 1999;Anzenbacher and Anzenbacherova, 2001;Zanger and Schwab, 2013), which are attached to membranes of the ER and mitochondria (Black, 1992).…”

Section: Positioning Of Microsomal P450s and Drugs In Lipid Bilayersmentioning

confidence: 99%

“…Most of the marketed drugs are amphiphilic compounds, and they have a large potential to accumulate in lipid bilayers (Seddon et al, 2009;Endo et al, 2011;Nagar and Korzekwa, 2012). It should be noted that the drug-metabolizing P450s catalyze the monooxygenase reaction as the most typical reaction.…”

Section: Positioning Of Microsomal P450s and Drugs In Lipid Bilayersmentioning

confidence: 99%

The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

Scott

Wolf

Otyepka

et al. 2016

Drug Metabolism and Disposition

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This symposium summary, sponsored by the ASPET, was held at Experimental Biology 2015 on March 29, 2015, in Boston, Massachusetts. The symposium focused on: 1) the interactions of cytochrome P450s (P450s) with their redox partners; and 2) the role of the lipid membrane in their orientation and stabilization. Two presentations discussed the interactions of P450s with NADPH-P450 reductase (CPR) and cytochrome b 5 . First, solution nuclear magnetic resonance was used to compare the protein interactions that facilitated either the hydroxylase or lyase activities of CYP17A1. The lyase interaction was stimulated by the presence of b 5 and 17a-hydroxypregnenolone, whereas the hydroxylase reaction was predominant in the absence of b 5 . The role of b 5 was also shown in vivo by selective hepatic knockout of b 5 from mice expressing CYP3A4 and CYP2D6; the lack of b 5 caused a decrease in the clearance of several substrates. The role of the membrane on P450 orientation was examined using computational methods, showing that the proximal region of the P450 molecule faced the aqueous phase. The distal region, containing the substrate-access channel, was associated with the membrane. The interaction of NADPH-P450 reductase (CPR) with the membrane was also described, showing the ability of CPR to "helicopter" above the membrane. Finally, the endoplasmic reticulum (ER) was shown to be heterogeneous, having ordered membrane regions containing cholesterol and more disordered regions. Interestingly, two closely related P450s, CYP1A1 and CYP1A2, resided in different regions of the ER. The structural characteristics of their localization were examined. These studies emphasize the importance of P450 protein organization to their function.

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“…Liver enrichment can result from active uptake (Chu et al, 2013), saturation of efflux (Swift et al, 2010), higher tissue binding (Nagar and Korzekwa, 2012), and/or sequestration into subcellular compartments such as liposomes or lysosomes (Nadanaciva et al, 2011). Expression of efflux transporters has been demonstrated in HepatoPac (Khetani and Bhatia, 2008).…”

Section: Downloaded Frommentioning

confidence: 99%

Bridging In Vitro and In Vivo Metabolism and Transport of Faldaprevir in Human Using a Novel Cocultured Human Hepatocyte System, HepatoPac

et al. 2013

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An increased appreciation of the importance of transporter and enzyme interplay in drug clearance and a desire to delineate these mechanisms necessitates the utilization of models that contain a full complement of enzymes and transporters at physiologically relevant activities. Additionally, the development of drugs with longer half-lives requires in vitro systems with extended incubation times that allow characterization of metabolic pathways for lowclearance drugs. A recently developed coculture hepatocyte model, HepatoPac, has been applied to meet these challenges. Faldaprevir is a drug in late-stage development for the treatment of hepatitis C. Faldaprevir is a low-clearance drug with the somewhat unique characteristic of being slowly metabolized, producing two abundant hydroxylated metabolites (M2a and M2b) in feces (∼40% of the dose) without exhibiting significant levels of circulating metabolites in humans. The human HepatoPac model was investigated to characterize the metabolism and transport of faldaprevir. In human HepatoPac cultures, M2a and M2b were the predominant metabolites formed, with extents of formation comparable to in vivo. Direct glucuronidation of faldaprevir was shown to be a minor metabolic pathway. HepatoPac studies also demonstrated that faldaprevir is concentrated in liver with active uptake by multiple transporters (including OATP1B1 and Na + -dependent transporters).Overall, human HepatoPac cultures provided valuable insights into the metabolism and disposition of faldaprevir in humans and demonstrated the importance of enzyme and transporter interplay in the clearance of the drug.

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Commentary: Nonspecific Protein Binding versus Membrane Partitioning: It Is Not Just Semantics

Cited by 60 publications

References 30 publications

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

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

The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

Bridging In Vitro and In Vivo Metabolism and Transport of Faldaprevir in Human Using a Novel Cocultured Human Hepatocyte System, HepatoPac

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