Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
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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

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

Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which T cell responses to various autoantigens, including DNA topoisomerase I (Topo I), have been implicated. We investigated whether dendritic cells, generally considered to be the most potent APCs for the initiation of immune responses, would present either of two forms of Topo I to T cells more efficiently than PBMC APCS: Using cells from healthy controls and SSc patients, several important observations were made. First, neither APC type was able to initiate T cell proliferative responses to full-length native Topo I unless exogenous IL-2 was added. This is in contrast to vigorous T cell proliferation in response to Topo I polypeptide fragments presented by either APC type. Second, T cell responses to the full-length form of Topo I presented by dendritic cells were considerably lower than responses to Ag presented by PBMC APCS: Finally, no secondary T cell responses were observed unless the same Ag/APC combination as that used in the primary stimulation was maintained. These data indicate that different peptides are generated based upon the form of the Topo I and the APC that processes it. Taken together, these results suggest that a very specific combination of antigenic form and APC may be involved in breaking tolerance to Topo I in the early stages of development of SSC:
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PMID:Distinct autoreactive T cell responses to native and fragmented DNA topoisomerase I: influence of APC type and IL-2. 1131 83

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