Transporter Single Nucleotide Polymorphisms Research Articles

Association of SNPs in zinc transporter genes on seminal plasma zinc levels in humans.

This study is to examine the effects of single nucleotide polymorphisms (SNPs) of SLC30A and SLC39A on seminal plasma zinc concentration. Blood and seminal plasma samples were collected from outpatients. SNPs of zinc transporters were analyzed by next Generation sequencing technology, and seminal plasma zinc concentration were determined by inductively coupled plasma optical emission spectrometry. Our date showed nine SNPs (SLC30A8 rs2466295, rs2466294, SLC30A10 c.-160C>G, SLC39A8 rs9331, rs9705, rs151392, rs151393, SLC39A11 rs9912126, SLC39A14 rs1051708) were significantly associated with seminal plasma zinc concentration, and 14 SNPs (SLC30A8 rs2466295, rs2466294, SLC30A10 c.-160C>G, SLC39A6 rs148550301, SLC39A8 rs9331, rs9705, rs151392, rs151393, SLC39A11 rs9912126, rs61736066, rs36041371 and SLC39A14 rs1051708, rs76963096, rs17060854) were found to be significantly associated with total zinc per ejaculate. The seminal plasma zinc concentrations and total zinc per ejaculate were associated with the number of SNPs, and decreased significantly when five SNPs (SLC39A8 rs9331, rs9705, rs151392, rs151393 and SLC39A14 rs1051708) were a combination of homozygous genotype. Our findings suggest that different zinc transporter SNPs may significantly affect seminal plasma zinc levels.

Effect of Polymorphisms in Drug Transporters on Cisplatin Efficacy and Nephrotoxicity in Paediatric Osteosarcoma

Introduction: Osteosarcoma (OS) is the most common type of primary bone tumor in children and adolescents. Chemotherapeutic resistance to cisplatin represents such a significant barrier in the successful treatment of Osteosarcoma. The degree of nephrotoxicity and drug resistance (poor tumor necrosis) is associated with cisplatin accumulation in cells which is governed by Copper transporter protein 1 (CTR1) and Organic cation transporter 2 (OCT2). This study aims to determine the allelic frequency of CTR1 and OCT2 single nucleotide polymorphisms (SNPs) in osteosarcoma patients. In addition, detect the relation between SNPs in transporters and cisplatin efficacy or nephrotoxicity.
 Methods: A group of 120 pediatric osteosarcoma patients was recruited and genotyped for CTR1, rs7851395, and OCT2 rs316019. We detected the allelic frequency of the two gene polymorphisms. We defined good responders versus poor responders depending on tumor necrosis parameters and looked at nephrotoxicity and serum electrolytes according to CTCAEv4 using the Chi-square test (c2) and Kruskal-Wallis value, the odds ratio and confidence interval were calculated too.
 Results: We found that the C allele in (rs316019) OCT2 polymorphism was the dominant allele, and patients with (C/C genotype) were the dominant genotype (72%). and the "A" allele is the dominant allele in (rs7851395) CTR1 and patients with (A/A genotype) were (39.5%).
 Conclusion: the study had found that the "C" allele is the dominant allele in (rs316019) OCT2 and the "A" allele is the dominant allele in (rs7851395) CTR1, the study didn't find any significant relation between CTR1, OCT2 polymorphisms and cisplatin response or nephrotoxicity and farther multi center studies need to be done.

Population Pharmacokinetics of Metformin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus: Simulation of Doses According to Renal Function

Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.

Irinogenetics: How Many Stars Are There in the Sky?

Irinogenetics: How Many Stars Are There in the Sky?

Pharmacogenomics of the OATP and OAT families.

Drug disposition is highly dependent on the interplay between drug metabolism and transport in organs such as the intestine, kidney, and liver. Genetically determined variation in drug transporter function or expression is now increasingly recognized to have a significant role as a determinant of intersubject variability in drug response. Similar to the discoveries of functional genetic variations in drug efflux transporters, such as multi-drug resistance proteins 1 and 2, there have been considerable advances in the identification of single nucleotide polymorphisms in transporters that facilitate cellular drug uptake. Among the uptake transporters, members of the organic anion-transporting polypeptides and organic anion transporters can mediate the cellular uptake of a large number of structurally divergent compounds. Accordingly, functionally relevant polymorphisms in these transporters may contribute to interindividual and interethnic variability in drug disposition and response. In this review, recent progress relating to pharmacogenomics of organic anion transporters will be outlined along with a compilation of currently known genetic polymorphisms.