Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.
BACKGROUND
CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity.


METHODS
Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC.


RESULTS
Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000.


CONCLUSIONS
We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.
Wasserman
E
E
FSMSIT, Hop Paul Brousse, Villejuif, France.
Myara
A
A
Lokiec
F
F
Goldwasser
F
F
Trivin
F
F
Mahjoubi
M
M
Misset
J L
JL
Cvitkovic
E
E
D001663:Bilirubin / Q000097:blood; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D005878:Gilbert Disease / Q000188:drug therapy* / Q000378:metabolism; D014453:Glucuronosyltransferase; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077150:Oxaliplatin; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D059004:Topoisomerase I Inhibitors; D000077150:Oxaliplatin; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D001663:Bilirubin; D002166:Camptothecin