Study On The Combination Of Danshan Agents On The Clinical Population Pharmacokinetic Characteristics Of Fluvastatin

Background:OTAP1B1 mediated the absorption of Fluvastatin, which single nucleotide polymorphisms affected pharmacokinetic parameters of FV. Our previous in vitro study showed Danshensu induced the expression of OATP1B1, but the impact on the transportion and metabolic of FV has not been reported in the literature. Danshen agents commonly combinated with FV used in clinical for treatment of hyperlipidemia, whether Danshen agents could affect pharmacokinetic parameters of FV in human body has not been reported also. This study aimed to explore the effect of OATP1B1 polymorphisms and combination with Danshen agents on the pharmacokinetic parameters of FV in patients with hyperlipidemia and data from clinical cases of patients was difficult to collect, so we used research idea of population pharmacokinetic and pharmacogenetics, to expand the study of the influence of Danshen agents on the clinical population pharmacokinetic characteristics of FV.Objectives:Clinical cases report and blood samples were collected in patients with hyperlipidemia by a multicenter clinical trail, then used the NONMEM software to establish the fluvastatin population pharmacokinetic model. Aimed to provide support for making clinical individualized dosing regimen.Methods:1. Established clinical trial of patients taking danshen agents combined FV, The clinical cases and blood samples were collected in patients with hyperlipidemia patiens were told to return to hospital to draw blood samples in the 14 th days, 21 th days and 28 th days.2. HPLC-MS/MS method for detection of plasma drug concentration of Fluvastatin was established. RFLP-PCR method were build up for the detection of mutations of the third exon 388G>A and the fifth exon 521T>C.3. Regard blood drug concentration of fluvastatin as the basis, we compared with the objective function value and fit goodness of the model of one compartment with first-order elimination characteristics choose the most excellent model structure. PPK base model of fluvastatin was established by NONMEM program, the effects on population pharmacokinetics of 45 factors was explored. The final PPK model was built up, bootstrap and visua inspection was used to evaluate Model fit goodness.4. Study on the influence of covariates on the FV pharmacokinetic parametersResults:1. 52 CRF, 164 blood samples were collected from patients with hyperlipidemia takeing fluvastatin. All of the 52 patients were Han nationality, male to female ratio was 23/29, average age was 61.86±9.06 years old.2. We established fluvastatin LC-MS/MS detection method in this research which has high sensitivity and specificity, the detection limit was 0.5ng/m L. The genetype of OATP1B1 388A>G and OATP1B1 521T>C of 52 patients with hyperlipidemia has been analysied by PCR-RPLF methods. The results showed that mutant of OATP1B1 388 A>G and OATP1B1 521T>C has 7, 9, accounting for all patients with hyperlipidemia 13.5%, 17.3% respectively3. The pharmacokinetics of fluvastatin could be described by a one compartment model, and the inter-individual variation was consistent with the multiplicative model. The final model showed that combinating with Danshen agents、Age、OATP1B1 388A>G、521T.>C affected PPK parameters. Typical values of clearance and volume of distribution were 0.116L/h and 4.16×103L.4. Combination with Danshen agents improved CL about 22%. Distribution volume of elder improved 75% than the young people. Mutants of OATP1B1 388 site lowed CL about 57%,, mutants of OATP1B1 521 site lowed V about 49.5%.Conclusion:1. The PPK model estatbished in this study has good stability, which could provide some help for clinical rational use of fluvasatin.2. Conbination with Danshen agents could significantly increase clearance of FV, may be associated with it induced expression of OTAP1B1.3. Distribution volume of elder markly improved than the young may be associated with the accumulation of body fat.4. OATP1B1 388 A>G significantly reduced clearance, 521 T>C significantly reduced volume, may be related to gene mutation reduced its transport activity.