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Title: The influence of pregnancy and oral contraceptive steroids on drug metabolism
Author: Neale, Michael Gordon
ISNI:       0000 0001 3440 428X
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1970
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Methods for the determination of the hydroxylation of biphenyl in rat liver and the glucuronidation of 4-methylumbelliferone in rat and rabbit liver preparations have been developed by the modification of existing methods. Using these methods, the activities of biphenyl-hydroxylase and 4-methylumbelliferone glucuronyl transferase and p-nitrobenzoic acid nitroreductase and cytochrome P450 have been determined in normal and pregnant rats. When expressed per gram of liver,biphenyl-4-hydroxylase, 4-methylumbelliferone glucuronyl transferase and cytochrome P450 were found to be decreased in the livers of 19-20 day, but not 15-16 day, pregnant rats. However, liver weight also increased so that the total liver content of these parameters was similar to that of non-pregnant animals; total microsomal protein and nitroreductase activity were increased. Pregnancy did not prevent the induction of these parameters with pheno-barbitone. None of these parameters is altered in the full-term pregnant rabbit, although the hydroxylation of coumarin is decreased. The action of hexobarbitone in full-term pregnant rats is prolonged, confirming the in vitro studies. The effects of pregnancy on hepatic microsomal enzymes could not be reproduced by pretreatment with progesterone or oestradiol, alone or combined, though both of these endogenous steroids, and also oral contraceptive steroids, inhibited the hydroxylation and nitroreduction in vitro. Pretreatment with high doses of chlormadinone, norgestrel, norethynodrel, ethynodiol or mestranol for eighteen days, did not alter any of the liver parameters, though a single dose of norethynodrel caused inhibition of biphenyl-4-hydroxylation at one and twenty-four hours after dosing. Eighteen days treatment with ethynodiol and mestranol combined, increased the hydroxylation. long-term oral administration of a low dose of chlormadinone or ethynodiol, but not norethynodrel, decreased the hydroxylation but none of the other parameters. Pretreatment of rats with oral contraceptive steroids, except chlormadinone, decreased the duration of action of hexobarbitone in vivo. A method for the determination of the urinary metabolites of phenacetin by gas chromatography has been developed by modification of previous methods. The pattern of excretion in pregnant and non-pregnant rats is similar. Humans on the "pill" possibly excrete more unchanged phenacetin and less conjugated N-acetyl-p-aminophenol than controls.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available