Effects of pregnancy on the metabolism of drugs in the rat and rabbit

Abstract

In rats 19–20 days pregnant, liver weight is increased by 40 per cent, cytochrome P-450 concentration is decreased by 25 per cent and the specific activities of 4-methylumbelliferone glucuronyl transferase and biphenyl-4-hydroxylase are reduced by 25 and 30 per cent, respectively; biphenyl-2-hydroxylase and p-nitrobenzoic acid reductase are not changed. In rats, 15–16 days pregnant, liver weight is increased by 33 per cent but the concentration of cytochrome P-450 and the specific activities of the drug microsomal enzymes are unchanged. Expressed as total amounts per whole liver, there is an increase in microsomal protein and nitro-reductase in both 15–16 and 19–20 day pregnant animals but no changes occur in cytochrome P-450, glucuronyl transferase or biphenyl hydroxylases. Hexobarbital administered to rats at doses related to pregnant body weight increases the sleeping-time from 50 min in non-pregnant animals to 110 min at full-term, but when administered on the basis of the non-pregnant body weight the duration of anaesthesia remains unchanged. Pretreatment of pregnant (19–20 days) and non-pregnant rats with phenobarbital leads to similar increases in microsomal protein (25 per cent) and nitroreductase activity (40 per cent); cytochrome P-450 is increased in non-pregnant animals (30 per cent) but not in the pregnant, although biphenyl-4-hydroxylase is increased in both to such extents as to annul the inhibitory effect of pregnancy. Pretreatment with methylcholanthrene gives rise to similar increases in cytochrome P-450 (30 per cent) and biphenyl-2-hydroxylase (10-fold increase) in both pregnant and non-pregnant rats and again increases biphenyl-4-hydroxylase so as to annul the effect of pregnancy. With rabbits, no change occurs in liver weight, microsomal protein, nitro-reductase, cytochrome P-450, or biphenyl-4-hydroxylase at full-term pregnancy, but glucuronyl transferase is reduced by 20 per cent, and coumarin-7-hydroxylase by 60 per cent. Pretreatment of rabbits with phenobarbital increases microsomal protein (15, 25 per cent), nitro-reductase (70, 80 per cent), cytochrome P-450 (130, 90 per cent), biphenyl-4- hydroxylase (50, 60 per cent), coumarin-7-hydroxylase (40, 150 per cent), and glucuronyl transferase (65, 15 per cent) in both non-pregnant and pregnant animals, respectively. The decrease during pregnancy of hepatic glucuronyl transferase is attributed to competitive inhibition by high levels of endogenous estrogenic and progestational steroids, but the decrease in the activities of the microsomal hydroxylating enzymes is attributed to the decrease in P-450, which may result from high levels of growth factors.