Drug metabolism and personalized therapy最新文献

Objectives: This study sought to identify potential pharmacogenetic associations of selected enzymes and transporters with type 2 diabetes (T2D). In addition, pharmacogenomic profiles, concentrations of asymmetric dimethylarginine (ADMA) or kidney injury molecule-1 (KIM-1), and several covariates were investigated.

Methods: Whole blood was collected from 63 patients, with 32 individuals with T2D. A pharmacogenomic panel was used to assay genetic profiles, and biomarker ELISAs were run to determine subject concentrations of ADMA and KIM-1. Additive genetic modeling with multiple linear and logistic regressions were performed to discover potential SNPs-outcome associations using PLINK.

Results: Ten SNPs were found to be significant (p<0.05) depending on the inclusion or exclusion of covariates. Of these, four were found in association with the presence of T2D, rs2231142, rs1801280, rs1799929, and rs1801265 depending on covariate inclusion or exclusion. Regarding ADMA, one SNP was found to be significant without covariates, rs1048943. Five SNPs were identified in association with KIM-1 and T2D in the presence of covariates, rs12208357, rs34059508, rs1058930, rs1902023, and rs3745274. Biomarker concentrations were not significantly different in the presence of T2D.

Conclusions: This exploratory study found several SNPs related to T2D; further research is required to validate and understand these relationships.

Objectives: To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios.

Methods: Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario.

Results: The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme.

Conclusions: The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

Objectives: Atorvastatin is commonly used medication to achieve low levels of low-density lipoproteins (LDL). Cholesteryl ester transfer protein (CETP) and LDL receptor (LDLR) genetic variants can affect the cholesterol transport and hence may affect on atorvastatin response. This study aimed to investigate the influence of LDLR AvaII, CETP TaqIb, and Rs1532624 on the efficacy of 20 mg atorvastatin among Jordanian hyperlipidemic patients.

Methods: One hundred and 50 blood samples were collected from hyperlipidemic patients in the University of Jordan Hospital. Polymerase chain reaction-restriction fragment length polymorphism was used for genotyping of LDLR AvaII and CETP TaqIb genetic variants. The genotyping of CETP Rs1532624 variant was done by Sanger DNA-Sequencing.

Results: LDLR AvaII and CETP TaqIb and Rs1532624 variants showed a significant (p value < 0.05) association with the baseline of the LDL at the time of diagnoses. On the other hand, none of the tested genetic variants showed a significant (p value>0.05) association with LDL reduction after atorvastatin therapy.

Conclusions: Results demonstrated a significant association between the LDLR AvaII and CETP TaqIb, and Rs1532624 genetic variants with the LDL baseline level. However, the atorvastatin therapy among hyperlipidemic patients of Jordanian origin was not affected by any of the tested variants.

Objectives: Pharmacogenomics can explain some of the heterogeneity of sulfonylurea (SU)-related hypoglycemia risk. Recently, a role of OATP1B1, encoded by SLCO1B1 gene, on SU liver transport prior of metabolism has been uncovered. The aim of the present study was to explore the potential association of SLCO1B1 c.521T>C polymorphism, leading to reduced OATP1B1 function, with SU-related hypoglycemia risk.

Methods: Study cohort consists of 176 type 2 diabetes patients treated with the SUs glimepiride or gliclazide. 92 patients reported SU-related hypoglycemia, while 84 patients had never experienced a hypoglycemic event. Patients were previously genotyped for CYP2C9 *2 and *3 variant alleles that lead to decreased enzyme activity of the SU metabolizing enzyme CYP2C9 and have been associated with increased SU-related hypoglycemia risk. SLCO1B1 c.521T>C polymorphism was genotyped by use of PCR-RFLP analysis.

Results: SLCO1B1 c.521TC genotype frequency was significantly lower in hypoglycemic cases than non-hypoglycemic controls (15.2% vs. 32.1%, p=0.008). In an adjusted model, c.521TC genotype significantly reduced the risk of hypoglycemia (OR 0.371; 95% C.I. 0.167-0.822; p=0.015). In CYP2C9 intermediate metabolizers (n=54) c.521TC genotype frequency was significantly decreased in cases compared to controls (3 out of 36 cases, 8.3% vs. 7 out of 18 controls, 38.9%, p=0.012). A similar albeit not significant difference of SLCO1B1 c.521TC genotype was present in CYP2C9 extensive metabolizers (n=120) (18.2% in cases vs. 30.8% in controls, p=0.113).

Conclusions: We have found a protective effect of SLCO1B1 c.521C variant on SU-related hypoglycemia risk both independently and in interaction with CYP2C9 phenotypes. Our results suggest a possible linkage of SLCO1B1 c.521T>C polymorphism with variants in other genes impairing OATPs expressed in pancreatic islets that could interfere with SU tissue distribution.

Parkinson disease (PD) is a major public health challenge as many of the current drugs used in its management provide symptomatic relieve without preventing the underlying cause of the neurodegeneration. Similarly, the non-motor complications of PD, especially the gastrointestinal tract (GIT) disturbance increases the disease burden on both the PD patient and caregivers. Different theories have been postulated regarding the mechanisms or pathways involved in PD pathology but gut-brain axis involvement has gained much more momentum. This pathway was first suggested by Braak and colleagues in 2003, where they suggested that PD starts from the GIT before spreading to the brain. However, human exposure to environmental toxicants known to inhibit mitochondrial complex I activity such as rotenone, paraquat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are well associated with PD. Several reports have shown that oral exposure of laboratory animals to rotenone causes mitochondria dysfunction, GIT disturbance, overexpression of alpha synuclein and microbiota imbalance. This review focuses on the mechanism(s) through which rotenone induces PD pathogenesis and potential for therapeutic small molecules targeting these processes at the earliest stages of the disease. We also focused on the interaction between the GI microbiota and PD pathology.

Objectives: A comparative dissolution kinetics test (CDKT) and bioequivalence studies of generic proton pump inhibitors (PPIs) do not model pharmacological acid suppression (PAS) and pathological duodenogastric reflux (PDGR). This study aimed to model them in CDKT to assess drugs stability and potential pantoprazole-clarithromycin interactions.

Methods: In CDKT, PDGR (dissolution medium pH 7.00 ± 0.05, preexposure at pH 1.20 ± 0.05) and PAS (pH 4.00 ± 0.05) were modelled for original pantoprazole (OP) and its generics (GP1-4). In CDKT with high-performance liquid chromatography, dissolution gastric medium in adequate (pH 4.00 ± 0.05) and inadequate (pH 1.20 ± 0.05) PAS were modelled for original clarithromycin (OC) and its generics (GC1-4).

Results: After exposure in pH 7.00 ± 0.05, pantoprazole was released from GP1 within 10 min in the amount of 68.8%. In рН 4.00 ± 0.05, 83.0% and 81.5% of pantoprazole were released from GP1 and GP4. When OP, GP2 and GP3 were placed in pH 7.00 ± 0.05, pantoprazole was released in amount: 99.4%, 88.0% and 98.2%. Clarithromycin releasing from OC, GC1, GC2, GC3, GC4 in pH 4.00 ± 0.05 was 93.5%, 91.6%, 92.9%, 79.4% and 83.0%. In pH 1.20 ± 0.05: 9.7%, 6.7%, 8.5%, 33.3%, 28.8%.

Conclusions: Destruction of enteric coats of some local pantoprazole generics in CDKT-models might be a potential factor for inadequate therapy.

Objectives: Patients undergoing cardiac surgery develop post-sternotomy pain syndrome. The aim of this study was evaluation of the influence of CYP2C9, PTGS-1 and PTGS-2 genes polymorphisms on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Methods: The study included 90 patients undergoing cardiac surgery. A real-time polymerase chain reaction was used for the detection of single nucleotide polymorphisms (SNP). Pain intensity was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury (AKI) was determined by Kidney Disease Improving Global Outcomes criteria.

Results: Pain intensity by the NRS score was significantly higher in patients with CYP2C9*3 АA genotype compared to АC genotype: 7 [1,10] and 6 [2,7] (p=0.003); 7 [1,10] and 6 [2,7] (p=0.04); 6 [0; 10] and 5 [2,6] (p=0.04); 5 [0; 8] and 3 [0; 8] (p=0.02), on days 1, 2, 3 and 5 in the postoperative period, respectively. GSRS score was higher in patients with CYP2C9*2 CT genotype compared to CС genotype: 19 [15; 42] and 18 [15,36] (p=0.04), respectively. There were no significant differences in the pain intensity, dyspepsia severity and AKI frequency in patients with homozygous and heterozygous genotypes for PTGS-1 rs10306135, PTGS-1 rs12353214, PTGS-2 rs20417.

Conclusions: CYP2C9*3 and CYP2C9*2 gene polymorphisms may affect efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Objectives: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events.

Methods: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed.

Results: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding.

Conclusions: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 -1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.