Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer

Abstract

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.

Figure 1

Pharmacokinetic profiles of patients who received irinotecan. (A) The profile of 24 patients without UGT1A1*28, UGT1A1*6 and UGT1A1*27 showed that SN‐38 glucuronide (SN‐38G) levels were higher than the SN‐38 levels reported in previous studies. Each data point indicates mean  SD. (B) The patient with colon cancer received irinotecan at a dose of 150 mg/m² in FOLFIRI. (C) The patient with gastric cancer received irinotecan at a dose of 70 mg/m² in IP. SN‐38G levels were lower than SN‐38 levels in these two patients who were heterozygous for UGT1A1*6 and UGT1A1*28.

Figure 2

Ratio of the area under the plasma concentration–time curve (AUC) for SN‐38 to the AUC for SN‐38 glucuronide (SN‐38G), used as a surrogate for UGT1A1 activity (AUC_SN‐38/AUC_SN‐38G). Results are shown according to UGT1A1 genetic profile for 45 Japanese patients who received various regimens of irinotecan chemotherapy. Open symbols in the figure represent the patients suffering from grade 4 neutropenia. Lines indicate median values. One patient was excluded because of an incomplete set of blood samples.