1 Blood concentrations of promethazine and promethazine sulphoxide have been measured following oral and intravenous administration of promethazine to seven healthy male volunteers. 2 Promethazine disposition is characterised by a large volume of distribution (1970 1) and a high blood clearance (1.141 min-'). 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. 3 Promethazine sulphoxide 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 intravenous data are compared. Evidence is presented to support the hypothesis that S-oxidation of promethazine is predominantly an hepatic event. The conclusions of previous investigators with regard to the role of the gut mucosa in S-oxidation of phenothiazines is critically assessed.
1 In order to assess the contribution of an active metabolite to the overall pharmacological response following drug administration it is necessary to characterise the metabolite concentration-time profile. The influence of route of drug administration on metabolite kinetics has been investigated by computer simulation. Comparisons between simulated profiles and published concentration-time data have been carried out. 2 A route dependence in metabolite concentration-time curves is readily apparent provided the metabolite kinetics are formation rate limited and the hepatic clearance of drug is greater than 25 1/h (medium to highly cleared). Oral drug adininistration produces a triphasic metabolite concentration-time profile whereas only two phases are discernable after intravenous drug administration. The magnitude of the difference in maximum metabolite concentration is directly proportional to the hepatic clearance of drug due to first-pass metabolite production. 3 The route dependence in the shape of the metabolite concentration-time curves is most dramatic when the absorption and distribution of drug and the elimination of metabolite is rapid. A reduction in the rate of either of these processes alters the shape of the metabolite concentration-time profile such that the consequence of first-pass metabolite formation may be reduced.
No abstract
DTP (dichlorophenyl-bis-triazolylpropanol) was evaluated as a probe of drug-cytochromes P450 interactions in vitro and in vivo. Studies with rat liver microsomes demonstrate that DTP shows similar P450 binding affinity to its analog, ketoconazole, as determined by P450 difference spectra and inhibition of the metabolism of methoxycoumarin. As a more polar azole, DTP shows less affinity for rat plasma albumin (fraction unbound 0.56) than ketoconazole (fraction unbound 0.037). DTP metabolism is simpler than that of ketoconazole, with only one pathway, N-dealkylation which removes a triazole ring to yield DTP glycol. This primary metabolite is further metabolised to a carboxylic acid, a glycol glucuronide and a third unknown secondary metabolite (probably an acid glucuronide). Over a dose range of 0.1-24mg/kg there is complete mass balance recovery in urine via the five metabolites and unchanged drug. However DTP metabolism is dose dependent and while the affinity of DTP for the cytochromes P450 carrying out the initial dealkylation is high (1.5 microM based on unbound blood concentration), the capacity of the reaction is low (1 nmole/min). Under linear conditions, metabolic clearance is low (19ml/h), but ten-fold higher than renal clearance. The liver is the major distribution site for both DTP and ketoconazole. At low DTP concentrations, a specific high affinity process dominates the hepatic binding of DTP resulting in a liver:blood partition coefficient of approximately 30. Hepatic binding is concentration dependent and the progressive decrease in partition coefficient observed as the dose of DTP is escalated is coincident with a decrease in volume of distribution. The two saturable processes involved in the disposition of DTP result in an unusual concentration dependency in the blood concentration-time profile of this azole. Following administration of a high dose (10mg/kg) of DTP the log concentration-time profile is sigmoidal. At high concentrations (above 1mg/L) both the N-dealkylation and the hepatic binding of DTP are saturated, but as concentrations fall to approximately 0.05mg/L the former process becomes linear and the time profile is convex over this concentration range. At later times as DTP concentrations decline further, the tissue binding also reaches the linear region and the time profile becomes concave. Only at low concentrations (below 0.05mg/L) do both processes become first order and the true half life is evident.
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