Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38

Luca Paoluzzi, Arun S. Singh, Douglas K. Price, Romano Danesi, Ron H.J. Mathijssen, Jaap Verweij, William D. Figg, Alex Sparreboom

Research output: Contribution to journalArticle

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Abstract

The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)7TAA (UGT1A1*28), UGT1A9 766G>A (D256N; UGT1A9*5), and UGT1A9 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (± SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 ± 6466 ng·h/mL and 629 ± 370 ng·h/mL, respectively, which is in line with earlier findings. For UGT1A9*5, no variant alleles were observed, whereas for UGT1A9*3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1*28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p = .022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)854-860
Number of pages7
JournalJournal of Clinical Pharmacology
Volume44
Issue number8
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

Fingerprint

irinotecan
Alleles
Heterozygote
Area Under Curve
Pharmacokinetics
Glucuronosyltransferase
Uridine Diphosphate

Keywords

  • Genetic variants
  • Irinotecan
  • Pharmacokinetics
  • SN-38
  • UGT1A1
  • UGT1A9

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Paoluzzi, L., Singh, A. S., Price, D. K., Danesi, R., Mathijssen, R. H. J., Verweij, J., ... Sparreboom, A. (2004). Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. Journal of Clinical Pharmacology, 44(8), 854-860. https://doi.org/10.1177/0091270004267159

Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. / Paoluzzi, Luca; Singh, Arun S.; Price, Douglas K.; Danesi, Romano; Mathijssen, Ron H.J.; Verweij, Jaap; Figg, William D.; Sparreboom, Alex.

In: Journal of Clinical Pharmacology, Vol. 44, No. 8, 01.08.2004, p. 854-860.

Research output: Contribution to journalArticle

Paoluzzi, L, Singh, AS, Price, DK, Danesi, R, Mathijssen, RHJ, Verweij, J, Figg, WD & Sparreboom, A 2004, 'Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38', Journal of Clinical Pharmacology, vol. 44, no. 8, pp. 854-860. https://doi.org/10.1177/0091270004267159
Paoluzzi, Luca ; Singh, Arun S. ; Price, Douglas K. ; Danesi, Romano ; Mathijssen, Ron H.J. ; Verweij, Jaap ; Figg, William D. ; Sparreboom, Alex. / Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. In: Journal of Clinical Pharmacology. 2004 ; Vol. 44, No. 8. pp. 854-860.
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abstract = "The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)7TAA (UGT1A1*28), UGT1A9 766G>A (D256N; UGT1A9*5), and UGT1A9 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (± SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 ± 6466 ng·h/mL and 629 ± 370 ng·h/mL, respectively, which is in line with earlier findings. For UGT1A9*5, no variant alleles were observed, whereas for UGT1A9*3, 1 patient with the variant allele was found (allele frequency, 0.633{\%}). The distribution of the UGT1A1*28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p = .022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics.",
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