The disposition of zomepirac was investigated in 18 patients with various liver diseases and in 10 healthy normal subjects in order to further test the hypothesis that glucuronidation of drugs may be spared in liver disease. Severity of the liver disease was assessed by the galactose elimination capacity. Following oral administration of zomepirac (200 mg), plasma and urinary drug concentrations were measured by high-pressure liquid chromatography. Urine was assayed before and after alkaline hydrolysis. The apparent oral clearance of zomepirac was 3.7 f S.D. 1.2, 3.0 f 0.8, and 1.8 f 0.6 ml.min-'.kg-' in normal subjects, patients with mild liver disease, and cases with cirrhosis, respectively. In patients with liver disease, the reduction in zomepirac clearance was significantly correlated with the abnormalities in galactose elimination capacity (r = 0.83, n = 18), suggesting that the functioning liver cell mass was the major determinant of the rate of zomepirac disposition. These results are not consistent with the original hypothesis but suggest that-in contrast to ether-glucuronidation-ester-glucuronidation may be abnormal in liver disease, Dosage adjustments may, therefore, be necessary in patients with cirrhosis of the liver.
Whereas oxidative Phase I biotransformation reactions in the liver seem to be impaired in patients with cirrhosis, some Phase I1 reactions, e.g., the glucuronidation of oxazepam (l), lorazepam (2), and morphine (3), have been reported to proceed normally despite advanced liver disease. Although the biochemical explanation for these observations is as yet hypothetical, it was concluded that glucuronidation reactions might be spared in liver disease, and that compounds undergoing glucuronidation for their elimination would represent the drugs of choice for such patients.
It should be realized, that oxazepam, lorazepam, and morphine are substrates for ether-glucuronidation, and the effect of liver disease on ester-glucuronidation has not as yet been adequately investigated. Studies were, therefore, designed with zomepirac as test compound to answer the question whether or not ester-glucuronidation might also be spared in cirrhosis. Zomepirac is a new nonsteroidal antiinflammatory compound which is eliminated from the organism almost exclusively by glu-curonidation to the corresponding ester-glucuronide [ (4, 5 ) , Figure 11. Furthermore, in order to properly define the state of the liver of each patient, the galactose elimination capacity and the bromosulfophthalein elimination rate constant were also assessed. The results suggest that in contrast to ether-glucuronidation, the rate of ester-glucuronidation may be reduced in cirrhosis in proportion to the diminution of the galactose elimination capacity.
INVESTIGATED SUBJECTS AND METHODS INVESTIGATED SUBJECTS
As a control group, we investigated 10 normal volunteers. At the time of the study, they were in good general health and had no clinical evidence of liver or kidney disease. Tests of total serum bilirubin, SGPT, alkaline phosphatase, fasting conjugated serum bile acids, prothrombin time, total proteins, serum electrophoresis, and serum creatinine were within normal limits. None was taking any drugs during the week before the test.