12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.
The pharmacokinetics of trimethobenzamide in healthy adult subjects were compared when Tigan was administered as a 300 mg oral capsule or a 200 mg (100 mg/mL) intramuscular injection. The time to reach maximum plasma concentration (Tmax) was about 30 minutes after intramuscular injection compared to about 45 minutes after oral capsule administration. The plasma concentration-time profile of trimethobenzamide was similar between the two formulations.
The major pathway of trimethobenzamide metabolism is through oxidation resulting in the formation of trimethobenzamide N-oxide metabolite. The pharmacologic activity of this major metabolite has not been evaluated.
Between 30 to 50% of a single dose in humans is excreted unchanged in the urine within 48 to72 hours.
Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28). Following a single 300 mg capsule oral administration, the respective mean (SD) Cmax of trimethobenzamide were 3.5 (1.1) and 4.2 (1.6) micrograms/mL in male and female subjects. The respective mean (SD) of AUC0–∞ of trimethobenzamide were 10 (2.7) and 10.4 (2.7) micrograms×hour/mL in male and female subjects.
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12). Following a single 300 mg capsule oral administration, the respective mean (SD) Cmax of trimethobenzamide was 3.8 (1.3) micrograms/mL in Caucasians and 3.9 (1.7) micrograms/mL in African Americans. The respective mean (SD) AUC0–∞ of trimethobenzamide was 10.4 (2.8) micrograms×hour/mL in Caucasians and 9.8 (2.5) micrograms×hour/mL in African Americans.