The excretion and metabolism of tritium-labelled loperamide was studied in male Wistar rats after an oral dose of 1.25 mg/kg. The results were compared with the data previously obtained, using loperamide-Jfl with the tritium-label in the metabolically unstable methyl groups of the tertiary amide. Loperamide and its metabolites were excreted mainly with the faeces. About 9% of the dose was excreted with the urine, predominantly as metabolites. Total excretion of radioactivity amounted to 93% of the dose within 4 days. Residual radioactivity in the tissues was negligible 4 days after treatment, indicating that loperamide and its metabolites did not accumulate in the tissues of the rat. Biliary excretion amounted to 56% of the dose up to 48 hours and consisted mainly of glucuronides of basic metabolites. The major metabolites in the urine were bis-desmethylated loperamide (R 21 345) and 4-(4-chlorophenyl)-4-hydroxy-piperidine (R 1 515). In the bile were present mono-and bis-desmethylated loperamide, whereas in the faeces a large part of the radioactivity was due to unchanged loperamide (about 30% of the dose). OxidativeN-dealkylation, including demethylation, seemed to be the major metabolic pathway.
Domperidone, a novel gastrokinetic and antinauseant lacking central side-effects, was administered intravenously to male Wistar rats and orally to fasted rats of either sex and to 1- and 6-day old neonates at doses of 2.5 mg 14C-labelled drug/kg. The biphasic absorption of domperidone in fasted rats was extremely rapid suggesting a partial absorption from the stomach. The metabolism of domperidone was sex- and age-related: it was slower in the female rat and in the neonates. The elimination system for the metabolites was still immature in the 1-day old pups. The distribution of domperidone (and related metabolites) to the rat brain was limited, brain concentrations being lower than corresponding plasma levels in all cases. In 1-day old neonates, the blood-brain barrier was less obstructive to the passage of domperidone than in older rats. In Beagle dogs, domperidone pharmacokinetics were described by a two-compartment model with half-lives of distribution and elimination of 6 minutes and 2.45 hours respectively. The time-courses of the drug plasma levels were similar for single and repeated (once daily for 11 months) doses of 2.5, 10 and 40 mg/kg, indicating that chronic administration of domperidone, even at high dose levels, did not alter its pharmacokinetics. AUC-values increased proportionally with the dose pointing to linear pharmacokinetics over a wide dose range.
Jan8 s e n P h a r m a c eutica Re s e a r c h Lab0 r a t o r ie s
INTRODUCTICNLorcainide monohydrochloride ( J a n s s e n P h a r m a c e u t i c a ,
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