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

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Abstract

Purpose

Propofol is one of the most widely used fast-acting intravenously administered anesthetics. However, although large inter-individual differences in dose requirements and recovery time have been observed, there are few previous studies in which the association between several potential covariates, including genetic factors such as the UGT1A9 and CYP2B6 genotypes, and propofol pharmacokinetics was simultaneously examined. This study aimed to identify factors determining propofol pharmacokinetics.

Methods

Eighty-three patients were enrolled, and their blood samples were collected 1, 5, 10, and 15 min after administering a single intravenous bolus of propofol at a dose of 2.0 ml/kg to measure propofol plasma concentration. Area under the time–plasma concentration curve from zero up to the last measurable time point (AUC15min) was determined from the concentration data. The inter-individual variability of the propofol pharmacokinetics was evaluated by investigating relationships between AUC15min and genotype of UGT1A9 and CYP2B6; clinical factors, such as age, sex, body mass index (BMI), and preoperative hematological examination; and hemodynamic variables measured by a pulse dye densitogram analyzer. The Spearman rank correlation coefficient and the Mann–Whitney U test were used for the statistical analysis of continuous and categorical values, respectively. Subsequently, clinical factors that had p values of < 0.05 in the univariate analysis were examined in a multivariate analysis using multiple linear regression analysis.

Results

Age, BMI, indocyanine green disappearance ratio (K-ICG), hepatic blood flow (HBF), preoperative hemoglobin level, and sex were correlated with AUC15min (p < 0.05) in univariate analysis. Multivariate analysis performed to adjust for age, BMI, K-ICG, HBF, preoperative hemoglobin level, and sex revealed only BMI as an independent factor associated with AUC15min.

Conclusions

This study demonstrated that BMI influences propofol pharmacokinetics after its administration as a single intravenous injection, while UGT1A9 and CYP2B6 SNPs, other clinical factors, and hemodynamic variables do not. These results suggest that BMI is an independent factor associated with propofol pharmacokinetics in several potential covariates.

Clinical trials registration number

University Hospital Medical Information Network (UMIN000022948).

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Acknowledgements

The accomplishment of this dissertation is the joint efforts of all colleagues in Tohoku University School of Medicine and Tohoku Medical Megabank Organization. First, we would like to acknowledge the expert assistance of Ms. Masae Kimura, Department of Integrative Genomics, Tohoku Medical Megabank Organization, who helped with the genomic analyses. Second, workmates in the Department of Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine have great help in conducting this study based on our protocol.

Funding

This study was funded by the Department of Anesthesiology and Perioperative Medicine Tohoku University School of Medicine, Sendai Japan.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Akihiro Kanaya & Masanori Yamauchi

  2. Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Toshihiro Sato, Hiroaki Yamaguchi & Nariyasu Mano

  3. Department of Integrative Genomics, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan

    Nobuo Fuse

Authors
  1. Akihiro Kanaya
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Correspondence to Akihiro Kanaya.

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Kanaya, A., Sato, T., Fuse, N. et al. Impact of clinical factors and UGT1A9 and CYP2B6 genotype on inter-individual differences in propofol pharmacokinetics. J Anesth 32, 236–243 (2018). https://doi.org/10.1007/s00540-018-2470-3

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  • DOI: https://doi.org/10.1007/s00540-018-2470-3

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