Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects.

We studied the pharmacokinetics of moguisteine, a racemic non-narcotic peripheral antitussive drug, in 12 healthy male subjects after a single oral administration of 200 mg. The unchanged drug was absent in plasma and urine of all subjects. Moguisteine was immediately and completely hydrolyzed to its main active metabolite, the free carboxylic acid M1. Therefore, we evaluated the kinetic profiles of M1, of its enantiomers R(+)-M1 and S(-)-M1, and of M1 sulfoxide optical isomers M2/I and M2/II by conventional and stereospecific HPLC. Maximum plasma concentrations for M1 (2.83 mg/l), M2/I (0.26 mg/l) and M2/II (0.40 mg/l), were respectively reached at 1.3, 1.6 and 1.5 h after moguisteine administration. Plasma concentrations declined after the peak with mean apparent terminal half-lives of 0.65 h (M1), 0.88 h (M2/I) and 0.84 h (M2/II). Most of the administered dose was recovered in urine within 6 h from moguisteine treatment. The systemic and renal clearance values indicated high renal extraction ratio for all moguisteine metabolites, and particularly for M1 sulfoxide optical isomers. Plasma concentration-time profiles and urinary excretion patterns for M1 enantiomers R(+)-M1 and S(-)-M1 were quite similar. Thus, for later moguisteine pharmacokinetic evaluations the investigation of the plasma concentration-time curve and the urinary excretion of the sole racemic M1 through non-stereospecific analytical methods may suffice in most cases.

Assay of moguisteine metabolites in human plasma and urine: conventional and chiral high-performance liquid chromatographic methods.

Moguisteine is a novel peripheral non-narcotic antitussive agent. Pharmacokinetic studies in animal and in man showed that no unchanged drug is present in plasma, urine and faeces after oral administration. The main active metabolite, M1, is the free carboxylic acid of moguisteine, which maintains a stereogenic centre and consists of R(+)-M1 and S(-)-M1 enantiomers. M1 is partly metabolized to M2, its sulfoxidation derivative. A conventional HPLC method is described for the simultaneous determination of M1 and M2 in human plasma and urine after administration of therapeutic moguisteine doses. Plasma samples, previously acidified with phosphoric acid, are extracted with dichloromethane; urine samples are analyzed after appropriate dilution with methanol. Chromatography is performed using a Lichrosorb RP2 column and a linear gradient. M1 enantiomers can be determined in plasma extracts and urine samples by a chiral HPLC method using a beta-cyclodextrin column. The analytical characteristics of both HPLC procedures proved to be adequate to analyze samples of subjects treated with therapeutic doses of moguisteine during clinical pharmacokinetic studies.