Effects of Liver Disease on the Disposition of Ciramadol in Humans

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Abstract
To determine the effects of liver disease on the disposition of ciramadol, an analgesic that undergoes ether glucuronidation, we studied its plasma pharmacokinetics in 10 patients with stable cirrhosis, 8 with acute viral hepatitis, and 16 age‐matched healthy controls. Renal excretion of the glucuronides was also determined. In healthy controls given a single intravenous dose of the drug the t1/2 was 3.4 ± 0.3 hrs and the systemic clearance was 668 ± 109 ml/min of which renal clearance was 320 ± 73 ml/min and non‐renal clearance 349 ± 74 ml/min. The corresponding values after an oral dose were similar. Renal clearance was related directly to the estimated creatinine clearance. Moreover, the renal clearance of ciramadol exceeded creatinine clearance, suggesting that the drug was excreted not only by glomerular filtration but also by tubular secretion. The systemic clearance of intravenous ciramadol was diminished by 40% in cirrhosis, P < 0.05, due to a reduction in renal clearance, while non‐renal clearance remained normal. Renal clearance of the inactive glucuronides, on the other hand, was not affected. In patients with acute viral hepatitis, systemic clearance was unchanged, but renal clearance of ciramadol tended to increase during the acute phase of the disease and to return toward normal after recovery. Renal excretion of the inactive glucuronides was decreased by 48% (P < .05). These findings suggest that the non‐renal ether glucuronidation of ciramadol remains intact in patients with stable cirrhosis or acute viral hepatitis. However, the renal clearance of the drug may be impaired in cirrhosis, but tends to be enhanced in acute hepatitis. Finally, the renal excretion of the parent compound may differ from that of its metabolites. Thus, ciramadol may be a suitable analgesic in patients with stable liver disease provided the kidneys are functioning normally.