Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Irinotecan (CPT-11) is an anticancer prodrug. It is converted by carboxylesterase to yield an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), which acts as a topoisomerase I inhibitor. Several oxidative metabolites of CPT-11 have been identified in humans, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin (NPC), generated by cytochrome P-450 3A4 (CYP3A4). Other minor metabolites in which metabolic pathways and biologic activities have not been identified also exist. To further investigate the metabolism of CPT-11 in human liver, we analyzed metabolites of CPT-11 in human hepatic microsomes using a high-performance liquid chromatography/mass spectrometry (HPLC/MS) system and detected a new metabolite that was the major one produced in the microsomal system. HPLC-tandem mass spectrometry (HPLC/MS/MS) analysis indicated that this compound was an oxidation product formed by the loss of two hydrogen atoms from the terminal piperidine ring. Kinetic analyses indicated that a single enzyme generated the metabolite, and we have identified this enzyme in two in vitro systems. The formation of the new metabolite was significantly inhibited by SKF525A, ketoconazole, and an anti-CYP3A4 antibody and catalyzed specifically by CYP3A4 expressed in insect microsomes. A significant correlation was observed between the generation of this metabolite and the CYP3A4 content in individual human hepatic microsomes. These findings indicate that this newly detected metabolite is a CYP3A4-generated product that may be produced in hepatic microsomes of patients treated with CPT-11.
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PMID:A new metabolite of irinotecan in which formation is mediated by human hepatic cytochrome P-450 3A4. 1160 29

Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.
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PMID:Influence of phenytoin on the disposition of irinotecan: a case report. 1199 Jun 99

Irinotecan or CPT-11 [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] is a derivative of camptothecine used in the treatment of advanced colorectal cancer. It requires activation to SN-38 (7-ethyl-10-hydroxycamptothecine) by carboxylesterase. Irinotecan and SN-38 are detoxified through two major metabolic pathways: the first one leads to oxidative degradation compounds, APC [7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine] and NPC [7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine], and involves cytochrome P450 (3A4 isoform); the second one leads to SN-38 glucuronide (SN-38G) and involves UDP-glucuronosyltransferase (UGT). Using human hepatic microsomes, we studied the interactions of 15 drugs of common use in colorectal cancer patients on these metabolic pathways. Only nifedipine had a significant effect on SN-38 formation, decreasing carboxylesterase activity by 50% at 100 microM and 35% at 10 microM. Three drugs had a significant effect on SN-38G formation: clonazepam increased UGT activity by 50% at 100 microM and 30% at 10 microM, and nifedipine and vinorelbine inhibited the activity by 65 and 55% at 100 microM, respectively, with no effect at 10 microM. Five drugs exerted a significant inhibition on SN-38 formation at 100 microM: clonazepam (70%), methylprednisolone (50%), nifedipine (80%), omeprazole (85%), and vinorelbine (100%). Only omeprazole and vinorelbine still exerted a significant inhibition at 10 microM (30 and 90%, respectively), whereas only vinorelbine had a significant effect at 2 and 0.5 microM (70 and 40%, respectively). In conclusion, potential clinical interactions with the metabolism of irinotecan are likely to be important for vinorelbine, which strongly inhibits irinotecan catabolism by CYP3A4 at clinically relevant concentrations, but not for the other drugs, which exert an effect at concentrations not achievable in patients.
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PMID:Determination of drug interactions occurring with the metabolic pathways of irinotecan. 1201 2

Irinotecan, a camptothecin analogue, is a prodrug which requires bioactivation to form the active metabolite SN-38. SN-38 acts as a DNA topoisomerase I poison. Irinotecan has been widely used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. However, large inter-patient variability in irinotecan and SN-38 disposition, as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan. Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy. Irinotecan is subjected to be shunted between CYP3A4 mediated oxidative metabolism to form two inactive metabolites APC or NPC and tissue carboxylesterase mediated hydrolysis to form SN-38 which is eventually detoxified via glucuronidation by UGT1A1 to form SN-38G. The pharmacology of this compound is further complicated by the existence of genetic inter-individual differences in activation and deactivation enzymes of irinotecan (e.g., CYP3A4, CYP3A5, UGT1A1) and sharing competitive elimination pathways with many concomitant medications, such as anticonvulsants, St. John's Wort, and ketoconazole. Efflux of the parent compound and metabolites out of cells by several drug transporters (e.g., Pgp, BCRP, MRP1, MRP2) also occurs. This review highlights the latest findings in drug activation, transport mechanisms, glucuronidation, and CYP3A-mediated drug-drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent.
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PMID:Lessons learned from the irinotecan metabolic pathway. 1257 Jul 20

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It bears a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo models. The target of drugs of the camptothecin family is DNA topoisomerase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stabilize the enzyme-DNA complex and prevent the religation of the single-strand breaks created by the enzyme, which are converted to double-strand breaks upon the collision with a replication fork during the S-phase. Resistance to irinotecan appears not to be mediated by P-glycoprotein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this interaction. As with all camptothecin derivatives, irinotecan contains a lactone ring that can be spontaneously and reversibly hydrolyzed to a carboxylate open ring form, which predominates at neutral and alkaline pH and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally considered as a prodrug of this compound. The carboxylesterase which carries out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which may explain the superiority of irinotecan over SN-38 in vivo. Further metabolism of SN-38 to a beta-glucuronide conjugate is a major pathway of detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinotecan involve oxidations occurring on the bis-piperidine rings, which are carried out by cytochrome P450. Irinotecan has shown an important activity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommended schedules: weekly administration of 125 mg/m(2) with a 2-week drug-free interval every 4 administrations or 3-weekly administration of 350 mg/m(2), a dose that can be increased to 500 mg/m(2) with the support of antidiarrhetics. Other possible indications of irinotecan include lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokinetics of irinotecan are characterized by a 2- or 3-compartment decay, with a terminal half-life of about 10 h, a total volume of distribution of 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is eliminated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminated at the same rate. APC, produced by the action of cytochrome P450, isoenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabolites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant relationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a potential use for monitoring of this drug.
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PMID:Pharmacology of irinotecan. 1498 54

Carboxylesterases metabolize ester, thioester, carbamate, and amide compounds to more soluble acid, alcohol, and amine products. They belong to a multigene family with about 50% sequence identity between classes. CES1A1 and CES2 are the most studied human isoenzymes from class 1 and 2, respectively. In this study, we report the cloning and expression of a new human isoenzyme, CES3, that belongs to class 3. The purified recombinant CES3 protein has carboxylesterase activity. Carboxylesterases metabolize the carbamate prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11; irinotecan) to its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I inhibitor. CYP3A4 oxidizes CPT-11 to two major oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC) and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC). In this study, we investigate whether these oxidative metabolites, NPC and APC, can be metabolized to SN-38 by purified human carboxylesterases, CES1A1, CES2, and CES3. We find that CPT-11, APC, and NPC can all be metabolized by carboxylesterases to SN-38. CES2 has the highest catalytic activity of 0.012 min(-1) microM(-1) among the three carboxylesterases studied for hydrolysis of CPT-11. NPC was an equally good substrate of CES2 in comparison to CPT-11, with a catalytic efficiency of 0.005 min(-1) microM(-1). APC was a very poor substrate for all three isoenzymes, exhibiting a catalytic activity of 0.015 x 10(-3) min(-1) microM(-1) for CES2. Catalytic efficiency of CES3 for CPT-11 hydrolysis was 20- to 2000-fold less than that of CES1A1 and CES2. The relative activity of the three isoenzymes was CES2 > CES1A1 >> CES3, for all three substrates.
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PMID:Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. 1510 Jan 72