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Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5.

Publication ,  Conference
Klees, TM; Sheffels, P; Thummel, KE; Kharasch, ED
Published in: Anesthesiology
March 2005

BACKGROUND: There is considerable unexplained interindividual variability in the clearance of alfentanil. Alfentanil undergoes extensive metabolism by cytochrome P4503A4 (CYP3A4). CYP3A5 is structurally similar to CYP3A4 and metabolizes most CYP3A4 substrates but is polymorphically expressed. Livers with the CYP3A5*1 allele contain higher amounts of the native CYP3A5 protein than livers homozygous for the mutant CYP3A5*3 allele. This investigation tested the hypothesis that alfentanil is a substrate for CYP3A5 and that CYP3A5 pharmacogenetic variability influences human liver alfentanil metabolism. METHODS: Alfentanil metabolism to noralfentanil and N-phenylpropionamide was determined in microsomes from two groups of human livers, characterized for CYP3A4 and CYP3A5 protein content: low CYP3A5 (2.0-5.2% of total CYP3A, n = 10) and high CYP3A5 (46-76% of total CYP3A, n = 10). Mean CYP3A4 content was the same in both groups. The effects of the CYP3A inhibitors troleandomycin and ketoconazole, the latter being more potent toward CYP3A4, on alfentanil metabolism were also determined. RESULTS: In the low versus high CYP3A5 livers, respectively, noralfentanil formation was 77 +/- 31 versus 255 +/- 170 pmol . min . mg, N-phenylpropionamide formation was 8.0 +/- 3.1 versus 20.5 +/- 14.0 pmol . min . mg, and the metabolite ratio was 9.5 +/- 0.4 versus 12.7 +/- 1.4 (P < 0.05 for all). There was a poor correlation between alfentanil metabolism and CYP3A4 content but an excellent correlation when CYP3A5 (i.e., total CYP3A content) was considered (r = 0.81, P < 0.0001). Troleandomycin inhibited alfentanil metabolism similarly in the low and high CYP3A5 livers; ketoconazole inhibition was less in the high CYP3A5 livers. CONCLUSION: In microsomes from human livers expressing the CYP3A5*1 allele and containing higher amounts of CYP3A5 protein, compared with those with the CYP3A5*3 allele and little CYP3A5, there was greater alfentanil metabolism, metabolite ratios more closely resembled those for expressed CYP3A5, and inhibitors with differing CYP3A4 and CYP3A5 selectivities had effects resembling those for expressed CYP3A5. Therefore, alfentanil is metabolized by human liver microsomal CYP3A5 in addition to CYP3A4, and pharmacogenetic variability in CYP3A5 expression significantly influences human liver alfentanil metabolism in vitro. Further investigation is warranted to assess whether the CYP3A5 polymorphism is a factor in the interindividual variability of alfentanil metabolism and clearance in vivo.

Duke Scholars

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

March 2005

Volume

102

Issue

3

Start / End Page

550 / 556

Location

United States

Related Subject Headings

  • Pharmacogenetics
  • Microsomes, Liver
  • Humans
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • Anesthesiology
  • Alfentanil
  • 3202 Clinical sciences
  • 1103 Clinical Sciences
 

Citation

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Klees, T. M., Sheffels, P., Thummel, K. E., & Kharasch, E. D. (2005). Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5. In Anesthesiology (Vol. 102, pp. 550–556). United States. https://doi.org/10.1097/00000542-200503000-00012
Klees, Theresa Mariero, Pamela Sheffels, Kenneth E. Thummel, and Evan D. Kharasch. “Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5.” In Anesthesiology, 102:550–56, 2005. https://doi.org/10.1097/00000542-200503000-00012.
Klees TM, Sheffels P, Thummel KE, Kharasch ED. Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5. In: Anesthesiology. 2005. p. 550–6.
Klees, Theresa Mariero, et al. “Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5.Anesthesiology, vol. 102, no. 3, 2005, pp. 550–56. Pubmed, doi:10.1097/00000542-200503000-00012.
Klees TM, Sheffels P, Thummel KE, Kharasch ED. Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5. Anesthesiology. 2005. p. 550–556.

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

March 2005

Volume

102

Issue

3

Start / End Page

550 / 556

Location

United States

Related Subject Headings

  • Pharmacogenetics
  • Microsomes, Liver
  • Humans
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • Anesthesiology
  • Alfentanil
  • 3202 Clinical sciences
  • 1103 Clinical Sciences