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Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo.

Methods

Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR).

Results

Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89–128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients’ sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time–plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup.

Conclusions

No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

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Abbreviations

CYP2B6:

Cytochrome P450 2B6

UGT1A9:

UDP-glucuronosyltransferase 1A9

SNP:

Single nucleotide polymorphism

PG:

Propofol glucuronide

1-OHPG:

4-hydroxypropofol-1-glucuronide

4-OHPG:

4-hydroxyporpofol-4-glucuronide

4-OHPGs:

Sum of 4-hydroxypropofol-1-glucuronide and 4-hydroxyporpofol-4-glucuronide

4-OHP:

4-hydroxypropofol (2,6-diisopropyl-1,4-quinol)

HLM:

Human liver microsomes

AUC20min :

Area under the time-plasma concentration curve measured over 20 min

ASA:

American Society of Anesthesiologists

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Acknowledgments

We thank Pharsight Corporation for approving the free Academic Research Node License for WinNonLin through the Pharsight Academic License program. This research was supported by grants from the Swedish Research Council and from Karolinska Institutet. We are indebted to Åsa Nordling for valuable aid in analyses of propofol metabolites.

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Author notes

  1. Masahiro Hiratsuka

    Present address: Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

Authors and Affiliations

  1. Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden

    Irena Loryan, Marja Lindqvist, Inger Johansson, Masahiro Hiratsuka, Jan Jakobsson & Magnus Ingelman-Sundberg

  2. Department of Clinical Chemistry, Erasmus MC Rotterdam, Rotterdam, The Netherlands

    Ilse van der Heiden & Ron HN van Schaik

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  1. Irena Loryan
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Correspondence to Magnus Ingelman-Sundberg.

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Irena Loryan and Marja Lindqvist contributed equally to this work.

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Loryan, I., Lindqvist, M., Johansson, I. et al. Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia. Eur J Clin Pharmacol 68, 397–406 (2012). https://doi.org/10.1007/s00228-011-1132-2

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