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Alleviation of side effects induced by irinotecan hydrochloride (CPT-11) in rats by intravenous infusion

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Abstract

Purpose

Irinotecan hydrochloride (CPT-11) is a potent topoisomerase I inhibitor and is established and used widely as an antitumor agent. However, it sometimes causes severe side effects such as myelosuppression and diarrhea. These dose-limiting toxicities prevent the adoption of CPT-11 in aggressive chemotherapy. Thus we sought to determine in a rat model whether extending the period of infusion of CPT-11 would ameliorate the adverse reactions.

Methods

CPT-11 was administered intravenously (i.v.) to rats at a dose of 60 mg/kg per day for four consecutive days as a bolus injection or as 3-, 8- or 24-h infusions, and then blood cell counts and the incidence of acute and delayed-onset diarrhea were monitored.

Results

Serious acute and delayed-onset diarrhea and marked decreases in the number of neutrophils and lymphocytes were observed in the bolus injection group. These symptoms were alleviated in the infusion groups with the degree of alleviation dependent on infusion time. In the bolus injection group, mucosal impairment of the cecal epithelium including wall thickening, edema, a decrease in the number and size of crypts, and the formation of a pseudomembrane-like substance was observed, whereas these changes were less severe in the infusion groups. Areas under the plasma concentration-time curves (AUCpla) of CPT-11 and its metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), differed little among the bolus injection group, and the 3-h and 8-h infusion groups. However, the AUCpla values of CPT-11 and SN-38 were significantly decreased and increased, respectively, in the 24-h infusion group. The maximum plasma concentrations (Cmax) of CPT-11 decreased with increasing infusion time, but those of SN-38 did not.

Conclusions

It was confirmed that the side effects of CPT-11 were alleviated by extending the infusion time. The pharmacokinetic parameters suggested that the Cmax of CPT-11 is closely related to the incidence and severity of adverse reactions such as myelosuppression and acute and delayed-onset diarrhea.

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Abbreviations

AUCcec :

Area under the cecal tissue concentration-time curve

AUCmar :

Area under the bone marrow tissue concentration-time curve

AUCpla :

Area under the plasma concentration-time curve

Cmax :

Maximum concentration

CLtot :

Total clearance

CPT:

Camptothecin

CPT-11:

Irinotecan hydrochloride [7-ethyl-10-(4-(piperidino)-1-piperidino)carbonyloxycamptothecin]

G-CSF:

Granulocyte colony-stimulating factor

HPLC:

High-performance liquid chromatography

i.v.:

Intravenous(ly)

MRT:

Mean residence time

SN-38:

7-Ethyl-10-hydroxycamptothecin

SN-38G:

SN-38 glucuronide

T1/2 :

Half-life

UGT:

UDP-glucuronosyltransferase

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Acknowledgements

We thank Tsuneo Matsumoto, Yuriko Nagata and Minoru Andoh for excellent technical assistance.

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Authors and Affiliations

  1. Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi, 186-8650, Tokyo, Japan

    Akinobu Kurita, Shoichi Kado, Norimasa Kaneda, Masaharu Onoue, Shusuke Hashimoto & Teruo Yokokura

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  1. Akinobu Kurita
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  2. Shoichi Kado
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  3. Norimasa Kaneda
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  4. Masaharu Onoue
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  5. Shusuke Hashimoto
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Correspondence to Akinobu Kurita.

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Kurita, A., Kado, S., Kaneda, N. et al. Alleviation of side effects induced by irinotecan hydrochloride (CPT-11) in rats by intravenous infusion. Cancer Chemother Pharmacol 52, 349–360 (2003). https://doi.org/10.1007/s00280-003-0682-0

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