Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral administration to man.

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Abstract
Promethazine, a member of the phenothiazine group of drugs, is commonly used in allergic conditions, as a sedative and hypnotic and as a premedicant in anesthesia and obstetrics. Blood concentrations of promethazine and promethazine sulfoxide were measured following oral and i.v. administration of promethazine to 7 healthy male volunteers. Promethazine disposition is characterized by a large volume of distribution (1970 l) and a high blood clearance (1.141 min-1). Less than 1% of the dose is excreted unchanged in the urine, therefore total body clearance is essentially metabolic clearance. In accord with this high clearance the oral availability of promethazine is only 25%. The absorption of promethazine from the gastrointestinal tract exceeds 80% in most subjects. Minimal metabolism by the gastrointestinal mucosa is implicated. Promethazine sulfoxide pharmacokinetics are consistent with a pronounced first pass effect. Although the area under the curve for this metabolite is not route dependent, there is a marked alteration in the shape of the metabolite curve when oral and i.v data are compared. S-oxidation of promethazine apparently is predominantly a hepatic event. The conclusions of previous investigators with regard to the role of the gut mucosa in S-oxidation of phenothiazines is critically assessed.

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