Influence of multiple dose activated charcoal on the disposition kinetics of irinotecan in rats.
BACKGROUND
The main clinical adverse effect of irinotecan (CPT-11) therapy is diarrhoea. Using a rat model, we attempted to study the effects of activated charcoal on the prevention of diarrhoea after a bolus dose of CPT-11, and also investigated the disposition kinetics of CPT-11 and its metabolite, SN-38, as well as SN-38 glucuronide (SN-38G) in the presence and absence of charcoal.


METHODS
Male Sprague-Dawley rats were given a daily oral dose of activated charcoal (Ultracarbon, 2.5 g/kg daily for 5 days) 10 min before an i.v. bolus injection of CPT-11 (60 mg/kg daily for 5 days; total dose 300 mg/kg); the control group was given CPT-11 alone. The pharmacokinetics of CPT-11, SN-38 and SN-38G were determined in both groups of rats on day 1. The incidence of diarrhoea was monitored throughout the course of the study.


RESULTS
There were no differences in the mean (+/- SD) C, (15.8 +/- 7.5 vs 12.1 +/- 3.3 microg/ml), t1/2 (2.2 +/- 0.7 vs 2.2 +/- 0.5 h), CL (5.7 +/- 2.1 vs 6.8 +/- 1.2 l/h/kg), Vd (1798 +/- 958 vs 2280 +/- 731 l/kg) or AUC0-infinity (11.8 +/- 3.9 vs 9.1 +/- 1.7 microg x h/ml) of CPT-11 after dosing with or without activated charcoal. Similarly, charcoal treatment had no effect on the disposition kinetics of SN-38 and SN-38G. A higher frequency of grade 3 diarrhoea was observed in the control group compared to the charcoal treatment group (log OR: -1.06; 95% CI: -2.25, 0.13) but this was only marginally statistically significant (p = 0.08).


CONCLUSIONS
These results suggest that multiple oral doses of activated charcoal do not modulate the clearance of CPT-11 and SN-38 in rats. The implication is that activated charcoal alone may not be very effective in preventing CPT-11-induced diarrhoea.
Balram
Chowbay
C
Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore. ctebal@nccs.com.sg
Zhou
Qing-Yu
QY
Cheung
Yin Bun
YB
Lee
Edmund J D
EJ
D000284:Administration, Oral; D000818:Animals; D000930:Antidiarrheals / Q000008:administration & dosage*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002606:Charcoal / Q000008:administration & dosage*; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D004347:Drug Interactions; D000077146:Irinotecan; D008297:Male; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley
D000930:Antidiarrheals; D000972:Antineoplastic Agents, Phytogenic; D002606:Charcoal; D000077146:Irinotecan; D002166:Camptothecin