1 Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. 2 Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. 3 After intravenous infusion of nicardipine at 5 mg-' for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. 4 With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. 5 Steady-state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10-40 mg three times daily. 6 Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.

Four human volunteers given a 30 mg oral dose of nicardipine hydrochloride containing 40 microCi of the 14C-labelled material achieved peak plasma levels of compound-related radioactivity within one hour of dosing. Parent compound comprised only a minor fraction of the circulating radioactivity indicating rapid first-pass metabolism. Plasma radioactivity declined to background levels within 96 h and was excreted both in the urine and faeces. Urinary excretion was the favoured route comprising about 60% of the dosed radioactivity. Mean total recovered radioactivity amounted to 94.8%. Both 1,4-dihydropyridine and pyridine metabolites of nicardipine hydrochloride were excreted in the urine. The major urinary metabolites, comprising some 36% of the radioactivity excreted in the 0-8 h post-dose period, were the glucuronide conjugates of +/- 2-hydroxyethyl methyl-1,4-dihydro-2,6-dimethyl-4(m-nitrophenyl)-3,5-pyridine dicarboxylate and its pyridine from 2-hydroxyethyl methyl-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine dicarboxylate.

1. The biotransformation of nafimidone, an imidazole-substituted anticonvulsant, has been studied by characterization of urinary metabolites in dogs, cynomolgus monkeys, baboons and man. 2. The biotransformation of nafimidone in these laboratory animals and man is initially very similar, in each case proceeding by reduction to the aliphatic alcohol metabolite, nafimidone alcohol or 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole. 3. Further transformation of this metabolite involves oxidation in the naphthyl and imidazole functions, and/or conjugation. 4. The dog differs from the higher primates in that no metabolic modification of the naphthyl group takes place, the major metabolite in the dog being the O-beta-glucuronide of nafimidone alcohol. 5. In higher primates and man two isomers involving dihydroxylation in the naphthyl ring--1-[2-hydroxy-2-(5,6- or 7,8-dihydroxydihydro-2-naphthyl)ethyl]imidazole--were tentatively identified. These species alone showed evidence of an imidazole linked N-glucuronide of nafimidone alcohol. 6. The possible occurrence of stereoselective metabolism by the introduction of a chiral centre at C-9 in nafimidone alcohol was indicated in human urine by the presence of both epimers of the O-beta-glucuronide of nafimidone alcohol in a 2:1 ratio.

Summary. The rate of prostaglandin E (PGE) production was measured in collagenase‐dispersed amniotic cells obtained from 14 women after spontaneous labour at term—seven after spontaneous preterm labour, nine after delivery by elective caesarean section at term and six after induction of labour at term. Cells were incubated with and without arachidonic acid and PGE was estimated by specific radioimmunoassay. Basal PGE output (pmol/106 cells per 3 h) was highest in the spontaneous labour group, 27·5 (SEM 5·5) and lowest in the preterm labour group, 4 (SEM 1·2) (P<0·001). Values in the elective section and induction groups were 13·6 (SEM 2·7) and 10 (SEM 3·1), respectively; these values were significantly higher than in the preterm labour group and the values after induction were significantly lower than after spontaneous labour. Addition of arachidonic acid resulted in a significant increase in PGE output in all groups, but the values after preterm labour remained significantly lower than those of any group at term. These data indicate that towards term there is a maturation in the PG synthetase activity of the amnion and that PGE output in this tissue is increased in spontaneous labour.