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Titolo:
CLINICAL PHARMACOKINETICS OF IRINOTECAN
Autore:
CHABOT GG;
Indirizzi:
INST GUSTAVE ROUSSY,PHARMACOL LAB,URA 147 CNRS,39 RUE CAMILLE DESMOULINS F-94805 VILLEJUIF FRANCE
Titolo Testata:
Clinical pharmacokinetics
fascicolo: 4, volume: 33, anno: 1997,
pagine: 245 - 259
SICI:
0312-5963(1997)33:4<245:CPOI>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACTIVE METABOLITE SN-38; DNA-TOPOISOMERASE-I; CELL LUNG-CANCER; CAMPTOTHECIN DERIVATIVE IRINOTECAN; EVERY 3 WEEKS; PERFORMANCE LIQUID-CHROMATOGRAPHY; METASTATIC COLORECTAL-CANCER; LIMITED-SAMPLING MODELS; HUMAN TUMOR XENOGRAFTS; ADVANCED SOLID TUMORS;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
113
Recensione:
Indirizzi per estratti:
Citazione:
G.G. Chabot, "CLINICAL PHARMACOKINETICS OF IRINOTECAN", Clinical pharmacokinetics, 33(4), 1997, pp. 245-259

Abstract

This article reviews the clinical pharmacokinetics of a water-solubleanalogue of camptothecin, irinotecan {CPT-11 or peridino)-1-piperidino]-carbonyloxy-camptothecin}. Irinotecan, and its more potent metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin), interfere with mammalian DNA topoisomerase I and cancer cell death appears to result from DNA strand breaks caused by the formation of cleavable complexes. The main clinical adverse effects of irinotecan therapy are neutropenia and diarrhoea. Irinotecan has shown activity in leukaemia, lymphoma and the following cancer sites: colorectum, lung, ovary, cervix, pancreas, stomach and breast,Following the intravenous administration of irinotecan at 100 to 350 mg/m(2) mean maximum irinotecan plasma concentrations arewithin the 1 to 10 mg/L range. Plasma concentrations can be describedusing a 2- or 3-compartment model with a mean terminal half-life ranging from 5 to 27 hours. The volume of distribution at steady-state (V-SS) ranges from 136 to 255 L/m(2) and the total body clearance is 8 to21 L/h/m(2). Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUG) of both irinotecan and SN-38 increase proportionally to the administered dose, although interpatient variability is important. SN-38 levels achieved in humans are about 100-fold lower than corresponding irinotecan concentrations, but these concentrations are potentially important as SN-38 is 100- to 1000-fold more cytotoxic than the parent compound. SN-38 is 95% bound to plasma proteins. Maximum concentrations of SN-38 are reached about 1 hour after the beginning of a short intravenous infusion. SN-38 plasma decay follows closely that of the parent compound with an apparent terminal half-life ranging from 6 to 30 hours. In human plasma at equilibrium, the irinotecan lactone form accounts for 25 to 30% of the total and SN-38 lactone for 50 to 64%. Irinotecan is extensively metabolisedin the liver. The bipiperidinocarbonylxy group of irinotecan is firstremoved by hydrolysis to yield the corresponding carboxylic acid and SN-38 by carboxyesterase. SN-38 can be converted into SN-38 glucuronide by hepatic UDP-glucuronyltransferase. Another recently identified metabolite is 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-cnrbonyloxy-camptothecin (APC). This metabolite is a weak inhibitor of KB cell growth and a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). Numerous other unidentified me tabolites have been detected in bile and urine. The mean 24-hour irinotecan urinary excretion represents 17 to 25% of the administered dose. Recovery of SN-38 and its glucuronide in urine is low and represents I to 3% of the irinotecan dose. Cumulative biliary excretion is 25% for irinotecan, 2% for SN-38 glucuronide and about 1% for SN-38. The pharmacokinetics of irinotecan and SN-38 are not influenced by prior exposure to the parent drug. The AUC of irinotecan and SN-38 correlate significantly with leuco-neutropenia and sometimes with the intensity of diarrhoea. Certain hepatic function parameters have been correlated negatively with irinotecan total body clearance. rt was noted that most tumour responses were observed at the highest doses administered in phase I trials, which indicates a dose-response relationship with this drug. In the future, these pharmacokinetic-pharmacodynamic relationships will undoubtedly prove useful in minimising the toxicity and maximise the likelihood of tumour response in patients.

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Documento generato il 28/11/20 alle ore 00:18:22