Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics

Although it is frequently stated that patients with cirrhosis are more sensitive to benzodiazepines, the relative roles of impaired elimination and altered responsiveness have not been clarified. We evaluated the pharmacokinetics, pharmacodynamics, and sensitivity to triazolam in six patients with clinically stable cirrhosis and six age-matched control subjects. Our findings show that there were no significant differences between the patients with cirrhosis and the control subjects in any of the pharmacokinetic parameters. Drug effect, measured as postural sway, was also similar in the patients with cirrhosis and control subjects; therefore the ratio of effect area under the curve to concentration area under the curve, a measure of sensitivity, did not differ significantly between the patients with cirrhosis and the control subjects. Because triazolam is metabolized by P4503A, we hypothesized that the effects of cirrhosis on drug metabolism may differ with respect to the specific P450 responsible for the oxidation of this drug. These effects may differ because of the relative sparing of a specific P450 and because of an extrahepatic site of metabolism.