Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics

Kanaya, Akihiro; Sato, Toshihiro; Fuse, Nobuo; Yamaguchi, Hiroaki; Mano, Nariyasu; Yamauchi, M.

doi:10.1007/s00540-018-2470-3

Cited by 9 publications

(11 citation statements)

References 31 publications

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“…[26]. In contrast, other studies reported no significant effects of these SNPs on propofol metabolism [7,8,10,24], which partially concur with our study.…”

Section: Discussioncontrasting

confidence: 57%

“…The biotransformation of propofol is greatly dependent on liver metabolism [17][18][19], and cytochrome P450 (CYP) 2B6 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A9, the main enzymes involved in propofol metabolism, are responsible for the hydroxylation and glucuronidation of propofol [20][21][22]. Single-nucleotide polymorphisms (SNPs) in CYP2B6 and UGT1A9 might contribute to the inter-individual variability in the rate of formation of propofol metabolites [21][22][23], while several studies reported no significant effect of these SNPs on propofol metabolism [7,8,10,24].…”

Section: Introductionmentioning

confidence: 99%

“…Although previous studies investigated the contribution of sex and polymorphisms of propofol metabolizing enzymes on propofol blood concentration under single intravenous bolus or short-term propofol infusion [7,8,[10][11][12][13][14][15][16], the influence of those factors on the accuracy of Diprifusor™ during long-term propofol infusion remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Regarding the pharmacokinetics of propofol, sex has been reported to influence propofol metabolism and the effect of propofol, in addition to age, height, and weight [5][6][7][8][9][10][11][12][13][14][15]: for example, propofol metabolism in women is faster than that in men, and women awake faster than men. For clinical factors, hemodynamic state might also affect the accuracy of the TCI system [16], because the clearance of propofol depends on the hepatic blood flow [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

et al. 2018

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Introduction: To examine whether sex and polymorphisms of cytochrome P450 (CYP) 2B6 and UDPglucuronosyltransferase (UGT) 1A9 affect the difference between predicted and measured plasma propofol concentration during continuous infusion by target-controlled infusion.Results: Blood samples of 69 patients (48 men and 21 women) were obtained at 4 h after initial propofol infusion. Percentage performance error (PE) was calculated to assess the difference between measured and predicted propofol concentration. Regression coefficients (β) and 95% confidence intervals (CI) of sex and the polymorphisms of CYP2B6 and UGT1A9 for PE were, separately and mutually, estimated with linear regression. Covariates included age and body mass index in the minimal adjusted model, and additionally included clinical factors (mean blood pressure, heart rate, volume of intravenous fluid, surgical site, surgical position, and pneumoperitoneum) in the full adjusted model. PE was higher in men than in women (28.7% versus 10.5%, p = 0.015). Female sex was inversely associated with PE: the minimal adjusted β = − 8.84 (95% CI, − 16.26 to − 1.43); however, the fully adjusted β with clinical factors became not significant. The average of PE did not differ between polymorphisms of CYP2B6 and UGT1A9, and β of CYP2B6 516G>T polymorphisms mutually adjusted with female sex was not significant. Mean blood pressure, heart rate, and volume of intravenous fluid were independently associated with PE in the full adjusted model. Conclusions: Under 4 h anesthesia with propofol target-controlled infusion in our population, sex differences appeared to exist in the propofol concentration, which might be largely mediated by clinical factors, such as hemodynamic status.

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“…[26]. In contrast, other studies reported no significant effects of these SNPs on propofol metabolism [7,8,10,24], which partially concur with our study.…”

Section: Discussioncontrasting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

et al. 2018

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“…26 In contrast, some studies have reported that CYP2B6 rs3745274 contributes little to the variation of drug effects of propofol. 3,[27][28][29][30] Our current results suggest that CYP2B6 rs3745274 and rs2279343 do not influence propofol susceptibility during the induction period of anesthesia.…”

Section: Discussionmentioning

confidence: 55%

GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility

Zeng

Cao

Chen

et al. 2022

PGPM

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To explore the effect of gene polymorphisms of propofol GABA A receptor and metabolic enzyme on drug susceptibility during the induction period of general anesthesia. Patients and Methods: A total of 294 female patients aged 18-55 years, ASA I-II, who underwent hysteroscopy with intravenous general anesthesia, were included in the study. Anesthesia was induced by continuous intravenous infusion of propofol at 40 mg•kg −1 •h −1 . Infusion of propofol was ended when both the Modified Observer's Assessment of Awareness/Sedation scale (MOAA/S scale) decreased to 1 and the BIS index decreased to 60. The time when the MOAA/S scale decreased to 1 and the time when BIS index decreased to 60 was recorded to assess the susceptibility to the sedation effect. The maximum decreased percentage in mean arterial pressure (MAP) within 5 minutes was recorded to assess the susceptibility of cardiovascular response. Venous blood of each patient was collected to identify the presence of genetic variants in the GABRA1, GABRA2, GABRB2, GABRB3, GABRG2, CYP2B6, and UGT1A9 genes using the Sequenom MassARRAY ® platform. Results: After receiving propofol infusion, carriers of polymorphic GABRA1 rs4263535 G allele required significantly less time for BIS decreased to 60, while carriers of polymorphic GABRB2 rs3816596 T allele required significantly more time for BIS decreased to 60, carriers of polymorphic GABRA1 rs1157122 C allele and carriers of polymorphic GABRB2 rs76774144 T allele had a significantly less change in MAP. Conclusion: GABRB2 rs3816596 and GABRA1 rs4263535 polymorphisms are associated with susceptibility to the sedation effect of propofol. GABRA1 rs1157122 and GABRB2 rs76774144 polymorphisms are associated with the degree of drop in blood pressure after propofol infusion.

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Model‐informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations

Zhang

Liu

et al. 2023

Biopharm & Drug Disp

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HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi-enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model-informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates.However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%-39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%-31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure-response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.

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Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics

Abstract: University Hospital Medical Information Network (UMIN000022948).

Cited by 9 publications

References 31 publications

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility

Model‐informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations

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