Characterization of Pharmacokinetics in the Göttingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach

Abstract

Purpose: This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Göttingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research.

Methods: The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes.

Results: Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human.

Conclusions: The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing.

Keywords: in silico; metabolism; minipig; pharmacokinetics.