Abstract

Background: Bioavailability (F) and clearance (CL) are two pharmacokinetic parameters difficult to differentiate from simple plasma measurement when a drug is administered orally. Venous (V) / artery (A) concentration ratio of a drug could be a reliable index of its CL if measurements of plasma concentration were performed during a period of time where the absorption process was not longer operative, then during a pure elimination phase.

Objective: A novel subrogate using two protocolized saliva samples sequentially collected (first, S1, and second, S2) was designed in order to replace V and A free plasma drug concentrations, respectively. Two drugs, phenytoin (PHT) and carbamazepine (CBZ), which are well-known for their inducer properties and their dose-dependent clearance variations, were studied taking into account the sex of individuals.

Setting and patients: A multicentre two-phase collaborative study was done. The first phase was performed with healthy volunteers in order to determine salivary pharmacokinetic parameters after single dose administration. Twelve volunteers (6 male and 6 female) received 400 mg of CBZ (2 tablets x 200 mg, immediate release product). Twenty four volunteers (10 male and 14 female) received 100 mg of PHT.

The second phase was carried out with epileptic patients under CBZ (11 male 15 female) or PHT (11 male and 11 female) monotherapy, in order to study dose-related and sex-related pharmacokinetic differences.

Main outcome measures: In the single dose trials, peaks (T_max, C_max) were computed directly from the data. Areas under concentrationtime curves (AUC_∞), AUC_∞xW (area corrected by weight) and half-lives (t_1/2) were calculated. In the case of CBZ, AUC_{CBZ-10,11- epoxide}/AUC_CBZ metabolic ratios were also calculated. After multiple dose administration, S1 and S2 trough morning drug concentrations were measured.

Results: C_max and AUC differed significantly between sexes for the two drugs after single dose administration. Nevertheless, the apparent clearance (CL/F) per unit of body weight did not differ (CBZ) or slightly differed (PHT) between sexes. Higher metabolic ratio for CBZ in women would lead to lower F and therefore lower CL in this gender. In the case of PHT, women would have either lower F or higher CL than men.

After multiple dose administration, S1/S2 saliva drug concentration ratio correlated positively with S2 for CBZ, showing that CBZ clearance increases with daily dose. Gender differences were also observed for CBZ-10,11-epoxide concentration, being bioavailability the main parameter responsible for this difference. S1/S2 saliva PHT concentration ratio correlated negatively with S2, showing that PHT clearance diminishes with dose as it has been previously reported. Since a significant difference was found for S1/S2 ratio between male and females, CL is the pharmacokinetic parameter influenced by gender in PHT disposition.

Conclusion: S1/S2 saliva drug concentration ratio was sensitive enough for detecting systemic clearance changes. Both CBZ and PHT would modify their bioavailability and clearance by inducing efflux transporter throughout chronic treatments, from the first dose to multiple dose administration.

Keywords: Saliva drug concentration, efflux transporter expression, sex of individuals, bioavailability, clearance, carbamazepine, Phenytoin