Effects Of OCT2, DRD2 And DRD3 Genetic Polymorphisms On Pharmacokinetics And Pharmacodynamics Of Pramipexole

Many reason can resulted in interindividual variability in drug response, such as year, sex, disease and genetics. Pharmacogenetics studies indicate that inherited variation of drug-metabolizing enzymes, receptors or transporters is the determination of interindividual variability in drug responsePramipexole, a novel non-ergot dopamine receptor agonist, has selective activity at the D2 subfamily of dopamine receptors (D2, D3 and D4 receptor subtypes), binding with higher affinity to D3 than to D2 or D4 receptor subtypes. It can be used alone in early Parkinson's disease and provide sufficient relief of symptoms. In addition, this drug is used as add on therapy to levodopa in patients with advanced Parkinson's disease. With long-term levodopa therapy, many patients will develop dyskinesias or motor fluctuations. Dopamine agonists mimic dopamine and act directly on dopamine receptors in the brain. They are not as effective as levodopa in controlling symptoms, but they have the benefit of postponing the need for levodopa therapy or reducing the amount of levodopa needed to control symptoms, which in turn may help delay the onset of levodopa-related side effects. Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%. Pramipexole is extensively distributed, having a volume of distribution of about 500 L range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers, pramipexole is secreted by the renal tubules mediated by the organic cation transport system. However, there is marked interindividual variability in therapeutic responses and adverse drug reactions to pramipexole. It is thought that genetic variations in the gene encoding transporter and dopamine receptor are important factors in determining interindividual variability in drug response. OCT2 mainly expressed in kidney, its substrate include many endogenous bioactive amines and clinically used drugs such as as dopamine, norepinephrine, cimetidine, procainamide and metformin. Recently, many SNP have been found in OCT2 gene, and there is significant ethnic difference in distribution of SNP. M165I and R400C were present only in the African-American population sample, and K432Q was present in both the African-American and Mexican-American population samples. A270S was present in all of the populations screened and had a particularly high allele frequency over all populations (12.7%). Function study showed that decreased inhibition of the A270S variant by TBA. IS Song reported that the Vmax of the c.808G>T variant was significantly lower compared with the reference. Clinical study showed that 808G>T variant influence the characteristic of metformin pk, sbjects with SLC22A2 808G>T variant genotypes had significantly higher Cmax and AUC values, but lower Cl/F), Vd/F values, as compared to the SLC22A2 reference genotype group, and it had the gene dose effect.Dopamine receptor belongs to the G protein coupled superfamily. Now five recepter (D1-D5) had been cloned. Based on their biochemical and physiological and pharmaolgical nature, they are divied into two subfamily: D1 and D2 subfamily.D1 subfamily include D1 and D5 which activate the adenylclase resulted in the increase the cAMP; and D2 subfamily include D2,D3 and D4 which inhibite the adenylclase resulted in the decrease the cAMP. The study between the correlation of DR and Parkinson'disease focused on DRD2 and DRD3. Several polymorphisms had been found in DRD2 including-141C Ins/Del variation in promoter, Taq1A RFLP, (CA)n STR, and three nonsynonymous mutation:Ser311Cys, Pro310Ser, Val96Ala.Studies have showed that DRD2 TaqIA polymorphism is associated with striatal dopamine D2 receptor density and affect the affinity for substrate. DRD3 gene located in chromosome 3. dopamine receptor D3 gene (DRD3) displays a number of single nucleotide polymorphisms(SNPs), and most frequently studied SNP is the Ser9Gly and MspI RFLP. A report using an in vitro expression system found that the receptors encoded by allele glycine demonstrated a significantly greater affinity for dopamineBased on these information, our studies aimed to clarify the frequency of OCT2 808G>T in healthy subjects and Parkinson's pations and evaluate the association between OCT2 808G>T mutation and genetic risk for Parkinson's disease. We also investigated the effect of OCT2 808G>T polymorphism on PK of pramipexole and the effect of the common variation of DRD2 and DRD3 on drug response in Parkinson's pation with pramipexole treatment.The present series studies found that:1) The frequencies of the OCT 808G>T variant alleles in healthy subjects and Parkinson's pations were 11.4% and 3.1% respectively. The frequencies in Parkinson's pations was significantly lower than in healthy subjects. It demonstrated that there was correlation between OCT2 808G>T mutation and genetic risk for Parkinson's, and the mutation may be a protective factor for Parkinson's disease.2) To develop a LC-MS/MS method for the determination of pramipexole in human plasma.3) OCT2 808G>T polymorphism had effect the pharmacokinetics of pramipexole. The Cmax and AUC in subjects carring variant allele were significantly higher than in wild type subjects and the CL/F was significant lower.4) DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. The response rates for pramipexole treatment was significantly higher in Ser/Ser group (60%) compared with the group containing Gly allel (13%). When the subjects were grouped by DRD2 Taq1A polymorphism, there were no significant differences among three Taq1A genotype. A large-scale and multi-dose group study in patients with parkinson'disease is necessary for evaluating the impact of the genetic polymorphisms of dopamine receptor on therapeutic effects of pramipexole.In conclusion, our study provide mechanism to the individual differences in drug response of pramipexole from molecular level, healthy subjects level and patientslevel and provided useful information for the clinical use of pramipexole. Before taking pramipexle patients were genotyped for OCT2,DRD2 and DRD3 and would get better therapeutic effect and little adverse reaction.