A new, pharmacologically active metabolite of cocaine, ethylcocaine, has been reported in individuals after concurrent use of cocaine and ethanol. Formation of ethylcocaine may contribute to the common coabuse of these two drugs and the apparent danger of this practice. We have identified a nonspecific carboxyl-esterase that catalyzes the ethyl transesterification of cocaine to ethylcocaine in the presence of ethanol. In the absence of ethanol, this human liver esterase catalyzes the hydrolysis of cocaine to benzoylecgonine, a metabolite that is inactive as a psychomotor stimulant. A second human liver esterase is also described. This enzyme catalyzes hydrolysis of cocaine to ecgonine methyl ester, also inactive as a stimulant. These two liver esterases may play important roles in regulating the metabolic inactivation of cocaine.

Experimental and more limited clinical studies have suggested that influenza vaccination may depress the oxidative hepatic metabolism of various drugs and lead to drug toxicity. The alleged mechanism is the formation of interferon and the resulting decrease in cytochrome P-450 available for drug oxidation. Because of the clinical and basic science implications of these reports, we undertook to study the effects of influenza vaccine on the metabolism of three commonly used drugs: chlordiazepoxide, theophylline, and lorazepam. Our healthy male subjects were studied just before and 1 and 7 days after vaccination. As expected, lorazepam metabolism, which proceeds by glucuronidation and not oxidation, was not altered by vaccination. Surprisingly, however, the oxidation of chlordiazepoxide was also not depressed by the vaccine. Theophylline oxidation, which proceeds primarily by microsomal oxidation (demethylation), was significantly decreased 1 day, but not 7 days, after vaccination. Serum alpha-interferon levels rose after vaccination for only about 8 hours, and levels of gamma-interferon rose to about 500 IU/ml at 24 hours, peaked at 72 hours, and returned to normal by 100 hours after dosing. It appeared that the higher the theophylline clearance before vaccination, the greater the degree of clearance depression after vaccination. Thus the inhibition of drug oxidation after influenza vaccination is selective and each drug should be studied individually. The degree of depression of theophylline clearance is small and transient and appears to be greater in subjects with higher prevaccination clearance.

Procainamide and cimetidine are eliminated in large part by the kidneys. Both are secreted by an active transport mechanism in the proximal tubule and each inhibits secretion of the other in the isolated, perfused rabbit tubule. In this study in man, cimetidine inhibited renal clearance of oral procainamide by 36%. This was associated with a 28% decrease in the ratio of systemic clearance of procainamide to bioavailability, an 18% decrease in the elimination rate constant, and a 24% prolongation of elimination t1/2. These results suggest that cimetidine increases plasma t1/2 and decreases systemic clearance of procainamide in part by inhibiting its active secretion by the kidneys.