Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosing.

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.

The effect of maternal diet during late pregnancy on postnatal changes in blood and liver metabolites and hepatic hydroxymethylglutaryl-CoA synthase activity in the offspring.

Both starvation of and feeding a high linoleic acid content diet to rats during late pregnancy resulted in marked differences in the metabolism of the fed offspring immediately after birth when compared to control neonates (mother fed the normal high carbohydrate content laboratory diet during pregnancy). In particular differences in postnatal changes in blood glucose, non esterified fatty acids and ketone bodies and in hepatic triglyceride content were observed. Many of the differences appeared to be related to the variations in blood and hepatic metabolites present at birth in the various groups of animals. A similar situation also existed with respect to postnatal changes in the activity of hydroxymethylglutaryl-CoA synthase.

The effect of maternal diet on maternal and fetal hepatic and brown adipose tissue lipogenesis and blood and tissue metabolites.

Both starvation of and feeding a high linoleic acid content diet to rats during late pregnancy resulted in (relative to stock diet fed controls) a decrease in maternal hepatic glycogen content and lipogenesis, reduced blood glucose levels and an increase in blood ketone levels whereas only fat feeding caused an increase in blood triglyceride levels and only starvation resulted in a decrease in the amount of brown adipose tissue. Maternal starvation resulted in decreased fetal body, liver and brown adipose tissue weights, diminished liver and brown adipose glycogen content and lipogenesis and lowered blood glucose levels. Both maternal fat feeding and starvation caused triglyceride accumulation in fetal liver, elevated blood ketone levels and an increased proportion of fetal liver and carcass fatty acids accounted for by linoleic acid.

Hepatic lipogenesis and ketogenesis in the mother and fetus during postmaturity in the rat.

Prolongation of pregnancy for 1.5 days by the injection of progesterone leads to a decrease in maternal liver glycogen content and an increase in blood ketones without alteration in the activity of hepatic hydroxymethylglutaryl-CoA synthase, an enzyme of ketogenesis. Fetal hepatic mitochondrial hydroxymethylglutaryl-CoA synthase activity increases with increasing postmaturity in a similar manner to that observed in normal neonates, suggesting that the factors necessary for enzyme induction are present in utero during postmaturity and that birth and the intake of the milk diet of suckling are not essential for increased enzyme activity. Hepatic in vivo lipogenesis is elevated in both mother and fetus during prolonged pregnancy and the results indicate that progesterone may have a specific effect on hepatic lipogenesis.

Hepatic mitochondrial fatty acid oxidation during the perinatal period in the rat.

1. The activity of hepatic mitochondrial carnitine acyltransferase I increases rapidly after birth, is high during the suckling period and falls after weaning. In contrast, carnitine acyltransferase II and acyl-CpA dehydrogenase exhibit few developmental changes. 2. These and previous studies indicate that outer mitochondrial membrane acyl-CoA synthetase and inner membrane carnitine acyltransferase I increase in activity after birth much more rapidly than to any other enzymes of fatty acid oxidation. 3. Studies of the 18 hr after caesarian delivery indicate that whereas the major increase in the activity of acyl-CoA synthetase occurs within 3 hr of birth the change in carnitine acyltransferase I activity is less rapid. 4. Prolonged pregnancy, starvation of the mother or feeding the mother a high polyunsaturated fat content diet resulted in increased activities of acyl-CoA synthetase and carnitine acyltransferase I in the fetal liver.