Pharmacogenetics-based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms.

Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role in GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from 53 patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy-Weinberg equilibrium. An one-compartment model with first-order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution, and clearance estimated were 0.44 h-1 , 86 L, and 17.3 × (estimated glomerular filtration ratio/89.58)1.04  L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism.

Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery.

OBJECTIVE: To evaluate the impact of advanced age on rocuronium kinetic disposition in ASA I-III patients undergoing elective surgeries. METHODS: Young adult (20-50 years, n = 15) and elderly patients (65-85 years, n = 14) submitted to surgery under general anaesthesia were investigated. All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol. Rocuronium-induced neuromuscular block was monitored by train of four stimulations of the adductor muscle of the thumb on the ulnar nerve. The pharmacokinetic parameters were calculated by non-compartmental analysis. The relationship between rocuronium plasma concentration and the neuromuscular blockade was described by a sigmoidal Emax model. KEY-FINDINGS: Elderly patients presented decreased Cl (2.1 ml/kg per min vs 2.8 ml/kg per min; P = 0.0123); increased AUC/dose (507.8 µg min/ml (mg/kg) vs 392.2 µg min/ml/(mg/kg); P = 0.0168) and reduced volume of distribution (285.4 ml/kg vs 435.6 ml/kg, P = 0.0434) compared to young adults. The concentrations required to achieve 50% of maximum neuromuscular block (EC50) were similar for young adult (338.8 ng/ml) and elderly (462.7 ng/ml) patients (P > 0.05). CONCLUSIONS: Elderly patients showed increased AUC/D and reduced total Cl compared to young adult patients due to the age-related reduced renal function. Differences in the PK-PD properties of rocuronium in elderly population are due to changes in drug disposition rather than to alterations in the sensitivity to the drug.

Impact of fraction unbound, CYP3A, and CYP2D6 in vivo activities, and other potential covariates to the clearance of tramadol enantiomers in patients with neuropathic pain.

The pharmacokinetics of tramadol is characterized by a large interindividual variability, which is partially attributed to polymorphic CYP2D6 metabolism. The contribution of CYP3A, CYP2B6, fraction unbound, and other potential covariates remains unknown. This study aimed to investigate the contribution of in vivo activities of cytochrome P450 (CYP) 2D6 and 3A as well as other potential covariates (CYP2B6 genotype to the SNP g.15631G>T, fraction unbound, age, body weight, creatinine clearance) to the enantioselective pharmacokinetics of tramadol. Thirty patients with neuropathic pain and phenotyped as CYP2D6 extensive metabolizers were treated with a single oral dose of 100 mg tramadol. Multiple linear regressions were performed to determine the contribution of CYP activities and other potential covariates to the clearance of tramadol enantiomers. The apparent total clearances were 44.9 (19.1-102-2) L/h and 55.2 (14.8-126.0) L/h for (+)- and (-)-tramadol, respectively [data presented as median (minimum-maximum)]. Between 79 and 83% of the overall variation in apparent clearance of tramadol enantiomers was explained by fraction unbound, CYP2D6, and CYP3A in vivo activities and body weight. Fraction unbound explained 47 and 41% of the variation in clearance of (+)-tramadol and (-)-tramadol, respectively. Individually, CYP2D6 and CYP3A activities were shown to have moderate contribution on clearance of tramadol enantiomers (11-16% and 11-18%, respectively). In conclusion, factors affecting fraction unbound of drugs (such as hyperglycemia or co-administration of drugs highly bound to plasma proteins) should be monitored, because this parameter dominates the elimination of tramadol enantiomers.