Ronald Scott Obach

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The ability to use vitro inactivation kinetic parameters in scaling to in vivo drug-drug interactions (DDIs) for mechanism-based inactivators of human cytochrome P450 (P450) enzymes was examined using eight human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C(max), estimated(More)
Twenty-nine drugs of disparate structures and physicochemical properties were used in an examination of the capability of human liver microsomal lability data ("in vitro T(1/2)" approach) to be useful in the prediction of human clearance. Additionally, the potential importance of nonspecific binding to microsomes in the in vitro incubation milieu for the(More)
The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI) was examined for over 40 drugs using seven human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C(max), estimated hepatic inlet C(max), fraction unbound, and fraction of the probe drug(More)
We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report(More)
Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus(More)
Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with(More)
Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years,(More)
The nonspecific, noncovalent binding of three drugs, imipramine, warfarin, and propranolol, to pooled human and animal liver microsomes has been determined using equilibrium dialysis in conditions where no cofactor (NADPH) was included in the incubation. The binding of warfarin was dependent upon both protein and drug concentration, whereas the binding of(More)
The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug-metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC-MS assay was developed for 1-phthalazinone, the aldehyde oxidase-catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for(More)
Cytochrome P450 2C8 is involved in the metabolism of drugs such as paclitaxel, repaglinide, rosiglitazone, and cerivastatin, among others. An in vitro assessment of 209 frequently prescribed drugs and related xenobiotics was carried out to examine their potential to inhibit CYP2C8. A validated sensitive, moderate-throughput high-performance liquid(More)