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Title: Prediction of drug dosage : studies with bilirubin and oxazepam
Author: Scott, A. K.
ISNI:       0000 0001 2422 8593
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1983
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Prediction of drug dosage is difficult because of interindividual variation in both pharmacokinetic and pharmacodynamic factors affecting the drug dose-response relationship. This leads to a high incidence of both adverse drug effects and underdosing. The aim of this thesis was to investigate the use of serum bilirubin measurement as a predictor of elimination of drugs by glucuronidation and to study interindividual variation of glucuronidation in health and disease states. The following results were obtained: 1) Serum unconjugated bilirubin measurement was found to be a simple index of hepatic enzyme induction by phenytoin and phenobarbitone. There was a significant correlation (r 0.68) between serum bilirubin and antipyrine half life. The ratio of conjugatod:unconjugated bilirubin appeared to be more useful than unconjugated bilirubin alone but required a more sensitive and specific assay for accurate measurement of bilirubin glucuronides. 2) Attempts were made to develop an HPLC assay for routine measurement of bilirubin. This has not been successful. Blanckaert et al (1980) used HPLC to show there is no conjugated bilirubin in serum from normal adults. Earlier techniques lacked specificity and resulted in false positive measurements for bilirubin conjugates. 3) Oxazepam was used as a model drug for glucuronidation. Widespread variation in elimination of oxazepam was observed. a) Oxazepam half life was reduced in patients treated with phenytoin alone or in combination with phenobarbitone. b) Hyperthyroid patients eliminated oxazepam more rapidly than when they were euthyroid after treatment. c) Hypothyroidism had no significant effect on oxazepam elimination. There was no significant correlation between serum bilirubin concentration and oxazepam elimination in these studies. Serum bilirubin is not useful as a marker substance for drug glucuronidation. Oxazepam is a safe and easily measured drug which merits further investigation as a marker drug for glucuronidation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry