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Lorazepam (Ativan) disposition and elimination were studied in 8 normal subjects before and after 1 wk of cimetidine therapy, 300 mg taken orally four times a day. In 4 of these 8 normal subjects the disposition and elimination of oxazepam (Serax) were also studied before and after similar treatment with cimetidine. Cimetidine did not alter the elimination of either lorazepam or oxazepam. Since both drugs are eliminated exclusively after conjugation as glucuronide, this study demonstrates a relative sparing of this pathway of biotransformation of drugs in subjects receiving cimetidine.

The disposition and elimination of meperidine (Demerol) were compared in drug and alcohol-free, age-matched groups of 15 normal volunteers and 14 patients with acute viral hepatitis, while controlling the urinary pH at 7.0 or greater. In the controls, the plasma half-life (t1/2(β)) for meperidine was 3.37 ± 0.82 hr (mean ± SD), while in hepatitis patients it was significantly prolonged to 6.99 ± 2.74 hr (P

Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p N -desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.