Determination of in vitro metabolism of new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine

Early understanding of the pharmacokinetics of drug candidates is essential during the evaluation of drug development process. DL76 1-[3-(4-tert-butylphenoxy)propyl]piperidine is a novel promising non-imidazole H3 receptor antagonist. Presented study was undertaken to compare with each other the predicted hepatic clearance values of DL76 calculated, using two most common mathematical models “well-stirred” and “parallel tube”, based on the data obtained in in vitro experiments. The metabolic intrinsic clearance of DL76 equaled to 0.4848 mL/min/mg protein was scaled up and the values of hepatic clearance estimated from "well-stirred" and "parallel tube" models were 55.47 mL/min/kg and 58.80 mL/min/kg, respectively. They were further compared with pharmacokinetic parameters calculated based on the concentration-time profile obtained following intravenous administration of DL76 to rats at the dose of 6 mg/kg. The estimated systemic serum clearance value of 144.5 mL/h/kg and blood clearance value of 81.17 mL/min/kg indicate the potential extrahepatic metabolism of the investigated compound. This study demonstrates the utility of rat liver microsomes for the prediction of DL76 hepatic clearance.