A novel simultaneous modeling approach to estimate linearity of pharmacokinetic parameters, including saturation of intestinal efflux, in the rat.

Abstract Introduction Various independent methods exist for the estimation of linearity of pharmacokinetic parameters in vivo. A novel simultaneous modeling approach has been developed in the rat that in combination allows estimation of the rate and extent of duodenal absorption, hepatic first pass extraction and saturation of potential dose-dependent duodenal bioavailability (saturation of intestinal efflux). Methods Simultaneous modeling of plasma concentrations of a Pfizer compound in the rat were conducted using NONMEM™ after (1) accelerated intravenous, intraduodenal, and intraportal infusions over 5 h and (2) 5-min intravenous infusions of 0.28 and 1.4 mg doses. Results The data was best described by a two-compartment linear pharmacokinetic model with good agreement between observed and model predicted plasma concentrations following the various routes of administration. Clearance was estimated to be linear up to plasma concentrations of 1200 ng/ml. The estimated rate constants (± asymptotic errors) for intraduodenal absorption (KA), movement of drug from plasma to tissue (K23) and movement of drug from tissue to plasma (K32) were 0.645 ± 0.107, 18.0 ± 2.98, and 2.02 ± 0.209 h − 1 , respectively. The rate constants for drug elimination from the central compartment (K20) after 5-min intravenous infusion or accelerated infusion were 3.24 ± 0.6 or 6.26 ± 1.64 h − 1 . The estimated maximal extent of first pass extraction was 17%. The model (including increasing duodenal bioavailability as the amount in the duodenum increases, from a minimum of 5% to a maximum estimated intraportal bioavailability value— 83%) indicated a saturable intestinal efflux process. Discussion This novel study design and the proposed method for data analysis provides a robust and efficient means for assessing the linearity of multiple pharmacokinetic processes while accounting for the multi-compartmental distribution characteristics of the test compound.