Non-linear fluvoxamine disposition

摘要: Aims To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers. Methods Ten healthy, non-smoking men were maintenance treatment with for 4 weeks. Eight subjects CYP2D6 extensive metabolisers (EMs) and two poor (PMs). As a measure CYP1A2 phenotype, paraxanthine/caffeine ratio saliva after intake caffeine was studied. The 25 mg day−1 first week, 50 mg day−1 second 100 mg day−1 third week 200 mg day−1 fourth divided daily doses. On seventh day every serum concentrations followed dose interval 12 h. After discontinuation treatment, 1 week. Results For each three two-fold increases dose, mean AUC increased 3.25-fold, 3.17-fold 3.14-fold, respectively (P<0.0001), indicating decrease oral clearance dose. elimination half-life based upon 12–48 h 32.1±11.0 h whereas 3–7 days significantly shorter, 15.8±4.2 h (means±s.d.; P<0.001). There no significant correlations between phenotype AUCs at different (r=−0.56; P=0.095 correlation 50 mg day−1 ). PMs had values same range as EMs. Conclusions The present conclusively demonstrates that exhibits non-linear kinetics within therapeutic interval. reason non-linearity is not Michaelis-Menten saturation single metabolic pathway, but rather complex involvement multiple parallel pathways.