The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries

Abstract

Purpose Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). Methods Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A,-1032G>A,-715T>C,-361G>A, and-189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. Results None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and-715T>C. A linkage disequilibrium was found between-1105G>A and-1032G>A genotypes. Patients genotyped as-A or AA (n = 17) for SLCO1A2-189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as −/− (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. Conclusion SLCO1A2-189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. Trial registration NCT 02399397 (ClinicalTrials.gov)

Polymorphisms contribute to differences in the effect of rocuronium in Chinese patients

“…Additionally, our results and those of Mei 8 indicate that OATP1B1 variants affect the clinical action of rocuronium. However, Costa and colleagues suggested that patients genotyped as ‐A or AA for SLCO1A2‐189_‐188InsA showed a reduction of total clearance of rocuronium compared to patients genotyped as ‐/‐ (151.6 vs. 207.1 ml/min) 7 . The findings of the current study do not support previous research.…”

“…According to our findings, the SLCO1A2 mutant decreased T2 and T4 of rocuronium compared with the major genotype. In addition, the latest study showed that the SNPs investigated by Costa 7 have not shown genome-wide significant evidence of association. 2 We also examined the role of SLCO1B3 SNPs in the metabolism of rocuronium, and the results showed no significant difference between the two groups.…”

“…6 In addition, recent studies have suggested that pharmacogenetic factors might explain part of the variation. 7,8 Previous studies have shown that SLCO1B1, ABCB1 and SLCO1A2 genetic polymorphisms affect the pharmacodynamics of rocuronium via hepatic uptake and biliary excretion of rocuronium. 7,8 Importantly, the mechanism of rocuronium in skeletal muscle relaxation is not negligible and even more important because mutations in rocuronium molecular targets and molecular binding site-related genes may be related to the sensitivity of rocuronium.…”

“…7,8 Previous studies have shown that SLCO1B1, ABCB1 and SLCO1A2 genetic polymorphisms affect the pharmacodynamics of rocuronium via hepatic uptake and biliary excretion of rocuronium. 7,8 Importantly, the mechanism of rocuronium in skeletal muscle relaxation is not negligible and even more important because mutations in rocuronium molecular targets and molecular binding site-related genes may be related to the sensitivity of rocuronium. Moreover, a previously study observed a phenomenon that interactions of rocuronium with drugs metabolized by CYP3A4.…”

Personalized Pediatric Anesthesia and Pain Management: Problem-Based Review

“…The duration of action may be prolonged from the usual 25-30 min to about 300 min in homozygotes with BChE deficiency [79,80]. Genetic variants in hepatocellular uptake protein OATP1A2 are known to influence biliary elimination of rocuronium [81].…”