UMLS:C0033036 - FACTA Search

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Query: UMLS:C0033036 (APC)
10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is a promising water-soluble analogue of camptothecin [S. Sawada et al., Chem. & Pharm. Bull. (Tokyo), 39: 1446-1454, 1991]. We have reported previously the presence of an important polar metabolite, in addition to 7-ethyl-10-hydroxycamptothecin (SN-38) beta-glucuronide, in samples of plasma taken from patients undergoing treatment with CPT-11 (L.P. Rivory and J. Robert, Cancer Chemother. Pharmacol. 36: 176-179, 1995; L. P. Rivory and J. Robert, J. Cromatogr., 661: 133-141, 1994). Plasma samples (0.5 ml) containing comparatively large amounts of this metabolite were extracted by solid-phase columns and subjected to high-performance liquid chromatography and mass spectrometry in parallel to fluorometric detection. The metabolite yielded [M + 1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11. Purified fractions were subjected to proton nuclear magnetic resonance, and the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycampothecin (APC), was further validated following synthesis. Like CPT-11, APC was found to be only a weak inhibitor of the cell growth of KB cells in culture (IC50, 2.1 versus 5.5 micrograms/ml for CPT-11 and 0.01 microgram/ml for SN-38, the active metabolite of CPT-11) and was a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). In contrast to CPT-11, APC was not hydrolyzed to SN-38 by human liver microsomes or purified human liver carboxylesterase. Furthermore, APC did not inhibit the hydrolysis of CPT-11 in these preparations. Interestingly, APC was only a weak inhibitor of acetylcholinesterase in comparison to CPT-11 and neostigmine. It appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo.
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PMID:Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. 870 9

This article reviews the clinical pharmacokinetics of a water-soluble analogue of camptothecin, irinotecan [CPT-11 or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy-camptoth eci n]. 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/m2, mean maximum irinotecan plasma concentrations are within the 1 to 10 mg/L range. Plasma concentrations can be described using 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 (Vss) ranges from 136 to 255 L/m2, and the total body clearance is 8 to 21 L/h/m2. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) 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 metabolised in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed 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]-carbonyloxy-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 metabolites 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 1 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. It 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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PMID:Clinical pharmacokinetics of irinotecan. 934 1

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.
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PMID:Critical issues in the evolving management of rectal cancer. 942 68

Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer. Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P. Rivory et al, Cancer Res., 56: 3689-3694, 1996). As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media. The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes. The formation of APC was characterized by the following parameters: Km = 18.4 +/- 1.4 and 39.7 +/- 11.6 microM; and Vmax = 26.0 +/- 0.6 and 13.4 +/- 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively. This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6beta hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM. Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively. These concentrations exceed those expected in vivo. APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.
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PMID:Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. 945 91

A new simple reversed-phase high-performance liquid chromatographic method was developed for the determination of irinotecan (CPT-11) and three metabolites in human plasma, urine and feces homogenate. The metabolites of interest were 7-ethyl-10-hydroxycamptothecin (SN-38), its beta-glucuronide derivative (SN-38G) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (RPR 121056A; also referred to as APC). Sample pretreatment from the various biological matrices involved a rapid protein precipitation with simultaneous solvent extraction of 250-microl aliquots of sample with 500 microl of methanol-5% (w/v) aqueous perchloric acid (1:1, v/v). Separation of the compounds was achieved on an analytical column packed with Hypersil ODS material (100X4.6 mm I.D., 5 microm), and isocratic elution with a mixture of methanol-0.1 M ammonium acetate containing 10 mM tetrabutylammonium sulphate (30:70, v/v), pH 5.3 (hydrochloric acid). The column effluent was monitored at excitation and emission wavelengths of 355 and 515 nm, respectively. Results from a 4-day validation study indicated that this single-run determination allows for simple, simultaneous and rapid quantitation and identification of all analytes with excellent reliability. The described procedure permits the analysis of patient samples, and will be implemented in future studies to investigate the complete metabolic fate and disposition of CPT-11 in cancer patients.
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PMID:Liquid chromatographic determination of irinotecan and three major metabolites in human plasma, urine and feces. 969 45

Irinotecan (CPT-11) is an analogue of 20(S)-camptothecin with promising activity against several tumor types. In patients, CPT-11 is metabolized to 7-ethyl-10-hydroxycamptothecin (SN-38) and to the beta-glucuronide of SN-38. Recently, we identified an additional metabolite of CPT-11, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC; L. P. Rivory et al. , Cancer Res., 56: 3689-3694, 1996). The aim of this study was to investigate the interrelationships of all four compounds to identify factors that might be responsible for the large interpatient variability in CPT-11 and SN-38 kinetics. The plasma kinetics of CPT-11, SN-38, the beta-glucuronide of SN-38, and APC were studied in 19 patients for a total of 33 cycles (115-600 mg/m2). Although the area under the concentration curves (AUCs) of all compounds studied increased with dose, there was considerable variability. Ratios of the AUCs of the appropriate compounds were used as estimates of the major routes of metabolism (conversion of CPT-11 to SN-38, metabolism of CPT-11 to APC, and glucuronidation of SN-38). Each ratio varied more than 10-fold across the patient population, and the apparent extent of conversion of CPT-11 to SN-38 was highest at the 115 mg/m2 dose level. Interestingly, AUCSN-38 was greater in patients with both high AUCCPT-11 and AUCAPC. We conclude that the variability of the pharmacokinetics of CPT-11 and SN-38 is likely to be due to extensive interpatient differences in the pathways implicated in the metabolism of CPT-11.
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PMID:Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. 981 8

The objective of this study was to determine the metabolic fate and disposition of the antitumor camptothecine derivative irinotecan (CPT-11). Ten patients with histological proof of malignant solid tumor received 200 mg/m2 CPT-11 as a 90-min i.v. infusion, followed by a 1.5-h i.v. infusion of cisplatin (60 or 80 mg/m2). Plasma, urine, and feces were collected for 56 h and analyzed by a specific reversed-phase high-performance liquid chromatographic assay for the parent drug and all four metabolites positively identified to date: SN-38; its beta-glucuronide conjugate, SN-38 beta-glucoronide (SN-38G); 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine (APC); and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine (NPC). A three-exponential decline was observed in plasma for all compounds, with a clear predominance of the parent drug [25.6+/-5.71 microM x h (CPT-11) versus 15.8+/-3.51 microM x h (total metabolites)]. Total urinary excretion was 28.1+/-10.6% of the dose, with unchanged CPT-11 and SN-38G as the main excretion products. Whereas renal clearance of SN-38 was only a minor route of drug elimination, fecal concentrations of this compound were unexpectedly high (on average, 2.45% of the dose), suggestive of intestinal hydrolysis of SN-38G by bacterial beta-glucuronidase. CPT-11 and the other metabolites could also be identified from fecal extracts, with a very minor contribution overall of the cytochrome P-450-mediated compounds 7-ethyl-10-[4-N-(1-piperidino)-1-amino]-carbonyloxycamptothecine and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine. Surprisingly, fecal excretion accounted for only 24.4+/-13.3% of the dose, leading to a total excretion of approximately 52%. These data indicate that half of the dose in urine and feces may constitute some further unknown nonextractable or nonfluorescent metabolites. The findings from this study should be of importance as a guide to further therapeutic evaluation of this drug.
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PMID:Irinotecan (CPT-11) metabolism and disposition in cancer patients. 982 38

The anticancer drug CPT-11 (7-ethyl-[4(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is a water-soluble derivative of camptothecin. We report here the conversion of APC (7-ethyl-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin), an inactive metabolite of CPT-11, to SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT-11, by a rabbit liver carboxylesterase. This reaction is not catalyzed by any known human enzyme. The formation of SN-38 from APC was characterized by an apparent Km of 37.9 +/- 7.1 microM and a Vmax of 16.9 +/- 0.9 pmol/units/min. SN-38 was confirmed as a reaction product by high-performance liquid chromatography and mass spectrometry. A 24-h incubation of 10 microM APC with 500 units/ml of rabbit carboxylesterase produced 4 microM SN-38. The product of this reaction inhibited the growth of U373 MG human glioblastoma cells in vitro. The IC50 for a 24-h exposure of U373 MG cells to APC in the presence of 50 units/ml of rabbit carboxylesterase was 0.27 +/- 0.08 microM, whereas APC alone demonstrated no inhibition of growth at concentrations up to 1 microM. The IC50 of U373 MG cells transfected with the cDNA encoding the rabbit carboxylesterase (U373pIRESrabbit) and exposed to APC for 24 h was 0.8 +/- 0.1 microM APC, whereas the growth of cells transfected with vector control (U373pIRES) was unaffected by up to 1 microM APC. Because APC is nontoxic to human cells, we are investigating the possibility of using APC/rabbit carboxylesterase in a prodrug/enzyme therapeutic approach.
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PMID:Conversion of the CPT-11 metabolite APC to SN-38 by rabbit liver carboxylesterase. 986 25

In this study, 11 patients with solid tumors were randomized to receive irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first course and the reversed sequence in the second course or vice versa. No significant differences in any toxicity were observed between the treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3 versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to single agent data and not significantly different between study courses (60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidinolcarbonyloxycamptothecine (APC), and 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were also sequence independent (P > or = 0.20). In addition, CPT-11 had no influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus 50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/- 1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of the combination CPT-11 and CDDP is schedule independent and that there is no mutual pharmacokinetic interaction.
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PMID:Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin. 1047 80

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11), a DNA topoisomerase I inhibitor, undergoes several metabolic pathways to generate conjugated and unconjugated derivatives that could be excreted from the body. The objective of this study was to determine the oxidative metabolites of CPT-11 recovered in human urine samples and to identify cytochrome P450 (CYP) involved in their formation. In addition to the already known metabolites of CPT-11 [SN-38, SN-38-G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized metabolites from the urine of two children and two adults given CPT-11. M1 and M2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moiety and on the terminal piperidine ring of CPT-11. M3 had a molecular mass of 602, but its urine concentration in patients was too low to establish its chemical structure by liquid chromatography/mass spectrometry. In vitro incubations with cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, or CYP3A7 did not produce any detectable metabolites. Only CYP3A4 produced both APC and NPC, resulting from the oxidation of the piperidinylpiperidine side chain of CPT-11 along with metabolite M2. The metabolism of CPT-11 by CYP3A5 was markedly different because neither APC or NPC nor M2 was produced, whereas only one new metabolite, M4 (molecular weight, 558), was generated by de-ethylation of the CPT moiety. No previous study has reported the presence of the M4 metabolite. Production of APC, NPC, M2, and M4 was prevented by ketoconazole, a specific CYP3A inhibitor. The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4. In conclusion, CYP3A plays a major role in the metabolism of CPT-11, with some differences of the metabolic profile exhibited by 3A4 and 3A5.
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PMID:Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. 1081 27

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