Absorption, distribution and excretion of 3H-labeled cephaeline- and emetine-spiked ipecac syrup in rats.

The maximum plasma radioactivity levels of tritium (3H)-labeled cephaeline, (24.3, 28.7 and 40.6 ng eq./mL) were reached at 2.00-3.33 hours following oral dosing of ipecac syrup. The maximum plasma radioactivity levels of 3H-emetine (2.71, 6.47 and 9.62 ng eq./mL) were reached at 1.08-2.33 hours following ipecac syrup administration. The Cmax values of 3H-cephaeline were followed by a biexponential decrease with half-lives t 1/2(lambda z) of 3.45-9.40 hours. On the other hand, the t 1/2 (lambda z)of 3H-emetine were 65.4-163 hours, which revealed a biexponential decrease. The radioactivity of both tritium-labeled compounds was distrbuted maximally in most tissues at 24 hours. For 3H-cephaeline, the maximum radioactivity levels in tissues were approximately 100-150 times greater than in plasma. For 3H-emetine, the radioactivity levels in tissues were approximately 1000-3000 times greater than in plasma. Tissue radioactivity levels decreased at a substantially slower rate than that observed in plasma. Tissue radioactivity of 3H-emetine decreased more slowly than that of 3H-cephaeline. For 3H-cephaeline, the cumulative biliary excretion of radioactivity was 57.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity in these rats was 16.5% and 29.1%, respectively, of the dose at 48 hours following dosing. For 3H-emetine, the cumulative biliary excretion of radioactivity was 12.5% at 48 hours. The cumulative urinary and fecal excretion of radioactivity was 9.4% and 34.1%, respectively, of the administered dose at 48 hours. The radioactivity level of 3H-emetine remaining in the carcasses at 48 hours was equivalent to approximately 50% of the dose. A portion of each tritium-labeled compound was subjected to entero-hepatic circulation. Thus, the absorption rate of 3H-cephaeline and 3H-emetine was estimated to be approximately 70% on the basis of the data obtained from excretion studies. There was no difference in the absorption process between these two compounds. However, the difference was admitted in the biliary clearance, which is the main excretion route of both compounds. Delayed excretion of 3H-emetine may be primarily due to its resorption as related to entero-hepatic circulation and tissue retention. This study has determined the absorption, distribution and excretion of 3H-cephaeline and 3H-emetine in rats.

Biotransformation of the ipecac alkaloids cephaeline and emetine from ipecac syrup in rats.

The metabolism of cephaeline and emetine, which are the primary active components of ipecac syrup, were investigated in rats. Cephaeline-6'-O-glucuronide was found to be a biliary metabolite of cephaeline. Cephaeline (6'-O-demethylemetine) and 9-O-demethylemetine were observed to be enzyme-hydrolyzed biliary metabolites of emetine. Cephaeline was conjugated to glucuronide, while emetine was demethylated to cephaeline and 9-0-demethylemetine, and may be conjugated to glucuronides afterwards. Urine, feces and bile were collected from rats within 48 hours following the administration of ipecac syrup containing tritium (3H)--labeled cephaeline or emetine. Metabolites were separated and quantified by thin layer chromatography (TLC) or high-performance liquid chromatography (HPLC). Biliary and urinary excretion rates of 3H-cephaeline were 57.5% and 16.5% of the dose, respectively. Cephaeline-6'-O-glucuronide was comprised 79.5% of biliary radioactivity and 84.3% of urinary radioactivity. Unchanged cephaeline was detected in 42.4% of the dose in feces. Biliary excretion rate of 3H-emetine was 6.9% of the dose. Emetine, cephaeline and 9-0-demethylemetine comprised 5.8%, 43.2% and 13.6% in hydrolyzed bile, respectively. There were no emetine-derived metabolites in urine or feces. The occurrence of unchanged emetine was 6.8% and 19.7% of the dose in urine and feces, respectively.

Single dose pharmacokinetics of syrup of ipecac.

Syrup of ipecac (SI) has been used medicinally since the 1500s; however, little is known about the pharmacokinetics in humans of SI's active ingredients, emetine and cephaeline. The objective of this study was to evaluate the rate of absorption and the rate of elimination of emetine and cephaeline. Ten healthy, adult, human volunteers between 18 and 45 years of age who were of ideal body weight (body mass index 20-25) completed this study. After an overnight fast, 30 mL SI were ingested. Blood samples were collected 30, 45, 60, 90, 120, 150, and 180 minutes post-ingestion and urine was collected throughout the study period. Plasma and urine concentrations of emetine and cephaeline were measured by reverse-phase HPLC with fluorescence detection. In virtually all subjects, emetine and cephaeline were detected within 5-10 minutes of dosing with the time to maximum concentration being approximately 20 minutes. The mean areas under the concentration-time curve (AUC) for both emetine and cephaeline were similar; however, the ratio of mean cephaeline maximum concentration (Cmax) to emetine Cmax was approximately 1.5. Four of the ten subjects exhibited a type of concentration-time profile in which the levels of cephaeline were substantially higher than those of emetine and the levels of cephaeline were substantially higher than noted for the other six subjects. In these remaining six subjects, the levels of emetine and cephaeline were lower than 10 ng/mL at all time-points. An initial elimination phase was noted in some subjects but not in others. Individuals in whom an initial elimination phase was not observed also exhibited low levels of both alkaloids as compared with the other subjects suggestive of a slower distribution phase. Less than 0. 15% of the administered emetine and cephaeline was recovered in the urine at 3 hours. No relationship between vomiting episodes and peak concentrations of emetine or cephaeline was found. Administration of SI results in rapid appearance and disappearance of emetine and cephaeline in plasma becoming almost undetectable at 3 hours. Very little of either alkaloid is eliminated in the urine within this time period, suggesting extensive distribution. The length of time that an administered dose of SI can result in the detection of emetine and/or cephaeline in the urine has not been determined; future studies in humans are required.