Sex‐differences in the disposition of substituted benzamides: Pharmacokinetics of a gastroprokinetic agent (4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl) ethoxy]‐N‐[2‐(diethylamino)ethyl] benzamide hydrochloride) (ML‐1035) in male and female New Zealand white rabbits

Abstract

The disposition of 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N- [2-(diethylamino)ethyl] benzamide hydrochloride (ML-1035) following intravenous (10 mg kg-1) and oral (200 mg kg-1) dosing was investigated in male and female New Zealand white rabbits. After intravenous dosing ML-1035 was eliminated with a half-life of 1.45 +/- 0.49 h in males and 0.79 +/- 0.08 h in females. Volume of distribution at steady-state was 2.08 +/- 0.98 l kg-1 in males and 9.11 +/- 5.86 l kg-1 in females. Clearance averaged 2.99 +/- 1.11 l h-1 kg-1 in males and 16.73 +/- 7.29 l h-1 kg-1 in females. All pharmacokinetic parameters were significantly different between males and females (p < 0.05). Absolute bioavailability after oral administration was 7.35 per cent for males and 12.31 per cent for females, suggesting that ML-1035 undergoes significant first-pass elimination. Plasma area under the curve for the metabolites of ML-1035 after both oral and intravenous administration were also different between the two sexes. These data suggest that the disposition of ML-1035 shows significant differences between male and female rabbits.

Biowaiver Monographs for Immediate Release Solid Oral Dosage forms: Metoclopramide Hydrochloride

“…14 Metoclopramide is conjugated with sulfuronic-and/or glucuronic acid, however, the major urinary metabolite is metoclopramide-N-4-sulfate. 41,45,46 According to Rao et al 48 pharmacokinetic parameters are significantly different between males and females. No results of in vitro transport studies in Caco-2 or other cell culture systems could be identified and no information about the intestinal absorption mechanism of the drug substance was found.…”