Disposition of antipyrine in patients with extensive metastatic liver disease

Abstract

In the present study the effect of metastatic liver disease on hepatic drug metabolism has been examined by studying the pharmacokinetics of antipyrine and the urinary excretion of antipyrine and its three major metabolites (4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine) in 12 patients with extensive metastatic liver disease, and in 12 matched healthy controls. In the patients total liver volume, the volume of the liver parenchyma, and the volume of the liver metastases were determined by computed tomography. The volume of liver metastases always exceeded 35% of the total liver volume. There were no significant differences between the patients and controls in plasma half-life, plasma clearance, or apparent volume of distribution of antipyrine. The cumulative urinary excretion of antipyrine and its three major metabolites was significantly lower in patients [44 (18) %] than in controls [71 (8) %]. The excretion of antipyrine itself was unchanged and the decrease in cumulative excretion was due to reduced excretion of the three metabolites. The results show that the activity of the hepatic mixed function oxidases was not impaired even in patients with extensive metastatic liver disease. This may be because liver metastases do not cause a corresponding reduction in the volume of normal hepatic parenchyma. The decreased urinary excretion of the three major metabolites of antipyrine, which are mainly glucuronidated, may have been due to an alteration in the process of conjugation.

Preoperative Galactose Elimination Capacity Predicts Complications and Survival After Hepatic Resection

“…11 In line with this concept, antipyrine clearance was maintained regardless of tumor burden. 55,56 However, in the latter study a decrease in conjugation reactions was found, suggesting that liver metastases could affect certain aspects of liver function. 56 Earlier studies found sulfobromophthalein clearance to be impaired in patients with hepatic metastases, 57 suggesting that unrecognized cholestasis could impair liver function.…”

“…55,56 However, in the latter study a decrease in conjugation reactions was found, suggesting that liver metastases could affect certain aspects of liver function. 56 Earlier studies found sulfobromophthalein clearance to be impaired in patients with hepatic metastases, 57 suggesting that unrecognized cholestasis could impair liver function. This contention is supported by the fact that even in the absence of metastasis, signs of cholestasis are often found in liver biopsy samples from patients with proven hepatic metastases.…”

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

“…[125][126][127] It has been suggested that a primary malignancy may itself cause changes in drug metabolism independent of coexisting liver metastases, and that liver metastases from different primary malignancies might affect drug metabolism in different ways.l128] Several recent studies of phenazone, aminophenazone and doxorubicin (adriamycin) elimination in patients with metastatic liver disease without cirrhosis showed that hepatic clearance in these patients was similar to that for healthy individuals. [28,128,129] Total phenazone clearance in metastatic liver disease was decreased in another study; however, the patients in this study also had cirrhosis.l I3O ] When expressed in terms of residual parenchymal cell mass, there was no difference in values between healthy individuals and those with metastatic disease.UF" This is consistent with the findings of Robertz-Vaupel et al, [128] who used computed tomography in patients without cirrhosis to show that there is substantial liver enlargement in metastatic liver disease, but that a large proportion of functional liver parenchyma still remains. As a result of this, drug elimination is not impaired.…”

“…As a result of this, drug elimination is not impaired. This is reflected in findings of normal CYP enzyme concentrations and normal in vitro drug metabolising enzyme activity in hepatic parenchymal samples from patients with metastatic liver disease.l 125,128] Limited studies in patients with primary liver carcinoma without cirrhosis suggest that phenazone clearance may be unaffected in these patients. [28,125] However, epirubicin clearance and the rate of formation of monoethylglycinexylidide from lignocaine are reduced in hepatocellular carcinoma, and the clearance of epirubicin correlates strongly with serum AST and serum albumin levels.U''!…”

Assessment of Doxylamine Influence on Mixed Function Oxidase Activity upon Multiple Dose Oral Administration to Normal Volunteers

“…Inclusion/exclusion criteria were established to avoid/minimize factors known to alter mixed function oxidase activity. 11,13,[27][28][29][30][31][32][33][34] These criteria included inclusion of healthy male volunteers, on a normal diet and within a narrow age range (i.e., 18-40 years), and exclusion of smokers, subjects with positive drug screens, and subjects exposed to enzyme inducers or inhibitors within 30 days prior to the study. In addition, normal renal function (creatinine clearance) was also required in order to meet the underlying assumptions necessary to estimate metabolite formation clearances.…”