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Titolo:
Irinotecan pharmacokinetics
Autore:
Chabot, GG; Robert, J; Lokiec, F; Canal, P;
Indirizzi:
Hop St Louis, INSERM, Ctr Hayem, U496, F-75475 Paris 10, France Hop St Louis Paris France 10 , Ctr Hayem, U496, F-75475 Paris 10, France Fdn Bergonie, Biochim Lab, F-33076 Bordeaux, France Fdn Bergonie Bordeaux France F-33076 ochim Lab, F-33076 Bordeaux, France Ctr Rene Huguenin, Lab Pharmacocinet, F-92211 St Cloud, France Ctr Rene Huguenin St Cloud France F-92211 inet, F-92211 St Cloud, France Inst Claudius Regaud, Lab Pharmacocinet, F-31052 Toulouse, France Inst Claudius Regaud Toulouse France F-31052 t, F-31052 Toulouse, France
Titolo Testata:
BULLETIN DU CANCER
, , anno: 1998,
pagine: 11 - 20
SICI:
0007-4551(199812):<11:IP>2.0.ZU;2-T
Fonte:
ISI
Lingua:
FRE
Soggetto:
ACTIVE METABOLITE SN-38; DNA-TOPOISOMERASE-I; CELL LUNG-CANCER; EVERY 3 WEEKS; CAMPTOTHECIN DERIVATIVE IRINOTECAN; PERFORMANCE LIQUID-CHROMATOGRAPHY; METASTATIC COLORECTAL-CANCER; LIMITED-SAMPLING MODELS; HUMAN TUMOR XENOGRAFTS; ADVANCED SOLID TUMORS;
Keywords:
irinotecan; CPT11; pharmacokinetics; pharmacodynamics; metabolism;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
117
Recensione:
Indirizzi per estratti:
Indirizzo: Chabot, GG Hop St Louis, INSERM, Ctr Hayem, U496, 1 Av Claude Vellefaux, F-75475 Paris Hop St Louis 1 Av Claude Vellefaux Paris France 10 75475 Paris
Citazione:
G.G. Chabot et al., "Irinotecan pharmacokinetics", B CANCER, 1998, pp. 11-20

Abstract

The clinical pharmacokinetics of irinotecan (CPT11) can be described by a 2 or 3 compartment model! a mean terminal half-life of 12 hours, a volume of distribution at steady state of 168 l/m(2) and a total body clearance of 15 l/m(2)/h. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and active metabolite SN38 increase proportionally to the administered dose, although interpatient variability is important. SN38 levels achieved in humans are about 100-fold lower than corresponding irinotecan levels, but these concentrations are important since SN38 is 100- to 1,000-fold more cytotoxic than the nt compound. SN38 is 95% bound to plasma proteins. SN38 plasma decay followsly that of the parent compound. Irinotecan is extensively metabolized in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by a carboxyesterase to yield the corresponding carboxylic acid and SN38. This metabolite ran be converted into SN38 glucuronide by UDP-glucuronyltransferase (1.1 isoform). A recently identified metabolite is the 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC), which is formed by the action of cytochrome P450 3A4. Numerous other unidenfitied metabolites are detected in bile and urine. The mean 24 h irinotecan urinary excretion represents 17-25% of the administered dose, whereas SN38 and its glucuronide recovery in urine is minimal (0.5 and 6%, respectively). Irinotecan and SN38 pharmacokinetics are not influenced by prior exposure to the parent drug. Irinotecan and SN38 AUCs correlate significantly with, leuko-neutropenia and sometimes with the intensity of diarrhea. Increased bilirubin levels appear to influence irinotecan total body clearance. The observation that most tumor responses were seen at the highest doses administered in phase I trials suggest a dose-response relationship with this drug. These pharmacokinetic-pharmacodynamic relationships may prove useful for abetter clinical management of this drug aimed nt a better control of toxicities and a better prediction of tumor response for the benefit of the individual patient.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 00:16:39