The Effect Of Flucloxacillin On CYP3A, P-gp Activity In Vivo And Its Relationship With MDR1 G2677T/C3435T (A)haplotype

Aims: To investigate the effect of flucloxacillin on CYP3A and Pgp in healthy volunteers, and to find out the differences of CYP3A and Pgp basal and induction phenotype between three known haplotypes of MDR1 gene.Methods: Genotypes were determined using the PCR-RFLP method. Suitable subjects have been selected out.:5 with 3435CC/2677GG, 5 with 3435TT/2677TT, 2 with 3435CC/2677AA. All subjects received 7.5 mg midazolam tablet and 100mg talinolol tablet on first day morning after fasting over night. Then blood samples were collected at 0-24 hours after taking the drug. The next week, each subject took flucloxacillin 500mg 4times a day. On day 9, all subjects received 7.5 mg midazolam tablet, 100mg talinolol tablet and 500mg flucloxacillin capsule in the morning after fasting over night. Then blood samples were collected at 0-24 hours after taking the drug. We use HPLC-MS-MS to detect the concentration of midazolam and concentration of 1-OH midazolam in 30 minuts, and use HPLC to detect the concentration of talinolol.Results: The AUC_{0 24} and AUC₀ of midazolam is changed from 341.73±110.12,346.13±110.01to218.02±56.84,211.92±56.76respectively(P＜0.05).Tmax is also changed significantly, from 0.57±0.10 to 0.34±0.05(P＜0.05). Besides, the concentration ratio of 1-OH midazolam and midazolam is increased from 4.30±0.75 to 8.16±1.39(P＜0.05). The AUC_{0 24} and AUC₀ of talinolol is altered from 4170.61±963.49, 5122.00±1494.4 to 2900.70±628.30, 3143.73±638.30(P＜0.05),with the changing of Cmax from 539.77±85.24 to 391.26±63.95(P＜0.05)together. The basal AUC₀ of midazolam and talinolol in subjects with 3435CC/2677GG; 3435TT/2677TT, 3435CC/2677AA is 212.98±35.80, 391.20±172.44,168.10±46.27; 4473.71±1109.73,3516.12±546.10, 8757.43±5635.41 respectively(P＞0.05).And the extend of induction in subjects with these three haplotypes is 0.15±0.09,0.45±0.40,0.45±0.45 respectively(P＞0.05).Conclusions: Flucloxacillin,a semi-synthetic isoxazolyl-penicillin,can significantly induce the activity of CYP3A and Pgp.Therefore,more attention should be paid when flucloxacillin is used in company with other drugs which are substrat of CYP3A or Pgp.In addition,we failed to find any difference of CYP3A and Pgp basal and induction phenotype between 3435CC/2677GG, 3435TT/2677TT, 3435CC/2677AA haplotype.