![]() Isoherranen N, Lutz JD, Chung SP, Hachad H, Levy RH, Ragueneau-Majlessi I. Clinical studies on drug–drug interactions involving metabolism and transport: methodology, pitfalls and interpretation. Tornio A, Filppula AM, Niemi M, Backman JT. A simple methodology to differentiate changes in bioavailability from changes in clearance following oral dosing of metabolized drugs. How transporters have changed basic pharmacokinetic understanding. Effects of drug transporters on volume of distribution. ![]() Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug-drug interactions are interpreted from drug development and regulatory perspectives. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. As V ss remains unchanged for intravenous metabolic drug-drug interactions, following oral dosing changes in V ss/F will reflect changes in F alone. Knowledge that V ss is unchanged in metabolic drug-drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. These results support the widely held founding tenant of pharmacokinetics that clearance and V ss are independent parameters. ![]() Changes in exposure (area under the curve) up to 5.1-fold were observed however, ratios of V ss changes have a range of 0.70-1.26, with one outlier displaying a V ss ratio of 0.57. Seventy-two metabolic drug interaction studies were identified where volume of distribution at steady-state (V ss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). For drugs that are not clinically significant transporter substrates, it is expected that drug-drug interactions would not result in any changes in volume of distribution.Īn evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug-drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms. It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. ![]()
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