The kinetic behavior of matrine in pig intestinal lumen after oral administration and its physiologically based pharmacokinetic modeling

TL;DR

This study examines how matrine behaves in the intestines of pigs after oral administration and creates a model to predict its concentration over time.

Contribution

The study introduces a minimal physiologically based pharmacokinetic model for matrine in pig intestinal lumen.

Findings

Matrine concentrations in the pig intestinal lumen peaked within 2 hours after oral administration.

The PBPK model accurately predicted matrine concentrations at most time points.

A dosage of 70 mg/kg every 8 hours is recommended for sufficient drug exposure.

Abstract

Matrine (MT) has been found to restore the susceptibility of Escherichia coli to a variety of antibiotics in vitro. Nevertheless, the absence of pharmacokinetic data makes it uncertain whether MT exhibits efficacy in vivo. The study aimed to investigate the kinetic behavior of MT in pig intestinal lumen, the primary site for the colonization of enterotoxigenic Escherichia coli, and to develop a minimal physiologically based pharmacokinetic (PBPK) model for MT in pig intestinal lumen.

Two animal experiments were carried out for these purposes. In experiment 1, 12 pigs were implanted with a sterile T-cannula, and then were given a single oral dose of MT or MT-Amoxicillin (AMO) combination at 40 or 70 mg/kg. In experiment 2, 25 pigs were administered with MT at 50 mg/kg/d by oral gavage for 5 d. Intestinal contents were collected at predetermined times and analysed by liquid chromatography tandem mass spectrometry (LC–MS/MS) method. The concentration-time data were analysed by non-compartmental method. Subsequently, a four-compartment PBPK model was developed and validated.

After oral administrations, the MT concentrations in pig intestinal lumen increased rapidly and reached their peaks within 2 h, then decreased in a two-phase decay pattern. The co-administered AMO did not alter the kinetic behavior of MT in pig intestinal lumen. The PBPK model gave an accurate prediction of MT concentrations in pig intestinal lumen at most time points.

A dosage regimen of 70 mg/kg every 8 h was recommended to ensure a sufficient drug exposure.

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