SN-38, an active metabolite of
irinotecan (CPT-11), is glucuronidated into
SN-38G mainly by UGT1A1, during detoxification. However, significant interindividual pharmacokinetic variability in
SN-38 is caused by factors, including inherited predispositions that may affect the function and expression of UGT1A1. Moreover, these individual differences can contribute to the development of clinical conditions, such as severe leucopenia and
diarrhea. Similar to
SN-38,
bilirubin is excreted into bile after being glucuronidated by UGT1A1. Thus,
bilirubin is metabolized by a mechanism similar to that of
SN-38. This suggests that the
bilirubin level may be an
indicator of the adverse effects caused by
CPT- 11. On the other hand, the ratio between the AUC of
SN-38 and the AUC of
SN-38G (AUCSN-38/AUCSN-38G) indicates the ability of
SN-38 to be glucuronidated, and is known to correlate with leucopenia and
diarrhea. However, many blood sampling points are required to calculate these AUCs. Therefore, the daily estimation of the AUCSN-38/AUCSN-38G values of individual patients is not practical at the clinical level. Thus, the objectives of this study were as follows: (1) to establish whether or not the total
bilirubin level is a useful
indicator in predicting the development of
CPT-11 toxicity. (2) to investigate the correlation of
SN-38/
SN-38G (the ratio of the serum concentrations of
SN-38 and
SN-38G) with AUCSN-38/AUCSN-38G. Based on the result of this investigation, it will be discussed whether or not
SN-38/
SN-38G may be used as an alternative to AUCSN-38/AUCSN-38G. This study included 14 patients with
small cell lung cancer or
non-small-cell lung cancer, in whom serum concentrations of
CPT-11,
SN-38, and
SN-38G were measured by HPLC. The results demonstrated a significant correlation between the total
bilirubin levels prior to
chemotherapy and the logarithmic values for AUCSN-38/AUCSN-38G (r2=0.852). Among the cases with high values for both the total
bilirubin level and the AUCSN-38/AUCSN-38G ratio, none of the patients had grade-3
diarrhea, while many cases tended to have grade-3 to -4
neutropenia. Additionally, the results of regression analysis suggest that
SN-38/
SN-38G (2 hr) and
SN-38/
SN-38G (4 hr) might be preferable as a predictive index for AUCSN-38/AUCSN-38G. These findings suggest that the total
bilirubin level and
SN-38/
SN-38G, 2 to 4 hours after administration might be used as indicators to predict CPT-11-induced
neutropenia. These indicators are likely to contribute to the pharmacogenetic analysis of UGT1A1 genes, as well as individualized
therapy, in future, and further studies on this subject are expected.