Oxidative Metabolic Bioactivation of Xenobiotics

Mabie, Stephane; Castagnoli, Kay; Castagnoli, Neal

doi:10.1201/b13995-3

Cited by 12 publications

(17 citation statements)

References 203 publications

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“…On the basis of previous experiences with peptide drug candidates containing less than 10 amino acids and that the degarelix molecule contains 7 non-natural amino acids, the peptide was subjected to stability studies in liver microsomes and hepatocytes as performed for a small molecule drug. However, degarelix was found to be a very poor substrate to any degrading enzymes, e.g., P450 enzymes (Mabic et al, 1999) present in the buffered liver microsome suspensions or in hepatocyte suspensions. The minor loss of degarelix in the rat microsomes could not be explained and was not further pursued.…”

Section: Discussionmentioning

confidence: 99%

Metabolite Profiles of Degarelix, a New Gonadotropin-Releasing Hormone Receptor Antagonist, in Rat, Dog, and Monkey

Sonesson

Koechling²,

Stalewski³

et al. 2011

Drug Metabolism and Disposition

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ABSTRACT:Degarelix is a novel competitive gonadotropin-releasing hormone receptor blocker (antagonist). In this study, the nonclinical metabolism and excretion of degarelix was investigated in SpragueDawley rat, beagle dog, and cynomolgus monkey. Degarelix was found to be stable when incubated in microsomes and cryopreserved hepatocytes from animal liver tissue. Absorption, distribution, metabolism, and excretion studies in male rat, dog, and monkey showed that after a subcutaneous dose of tritium-labeled degarelix, the peptide was rapidly absorbed with C max in plasma of 1 to 2 h. The predominant route of excretion was via the kidneys and the bile. In rat and dog, most of the degarelix dose was eliminated within 48 h via urine and feces in equal amounts (40-50% in each matrix), whereas in monkey the major route of excretion was fecal (50%) and renal (22%). In plasma and urine samples from all three species, mainly intact degarelix was detected. In bile and feces samples from rats and dogs, the same truncated peptides of the parent decapeptide were detected. The major metabolites identified represented the N-terminal tetrapeptide, the pentapeptide, and the heptapeptide. From the animal studies, it could be concluded that degarelix is subject to common peptidic degradation in the liver and bile and is fully excreted via metabolic and biliary (as metabolites and parent compound) and urinary (mainly as parent compound) pathways. Systemic exposure to metabolic products seems to be low.

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Section: Discussionmentioning

confidence: 99%

Metabolite Profiles of Degarelix, a New Gonadotropin-Releasing Hormone Receptor Antagonist, in Rat, Dog, and Monkey

Sonesson

Koechling²,

Stalewski³

et al. 2011

Drug Metabolism and Disposition

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“…As shown in Fig. 5, during the formation of 9-OH-CPT, the arene ring oxide was proposed to be an intermediate product according to the literature about the bioactivation of the arenes (Mabic et al, 1999).…”

Section: Metabolites Of 9-nitro-20(s)-camptothecin In Ratsmentioning

confidence: 99%

Identification of the Metabolites of 9-Nitro-20(s)-Camptothecin in Rats

Li¹,

Chen²,

Zhong³

et al. 2003

Drug Metabolism and Disposition

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ABSTRACT:9-Nitro-20(S)-camptothecin is a novel anticancer drug. In this study, metabolites of 9-nitro-20(S)-camptothecin in rats were identified. Rats were dosed with the drug, and the metabolites in the bile were isolated and collected by high-performance liquid chromatography using a gradient elution. By LC/MS n (n ‫؍‬ 1-3), the biliary metabolites in addition to the unchanged drug were identified as 9-amino-20(S)-camptothecin (M3) 20(S)-Camptothecin (CPT 1 ), a natural alkaloid extracted from the leaves and fruit of Camptotheca acuminata, is an inhibitor of DNA synthesis. It results in single-strand DNA break and finally in cell death, by reversibly stabilizing the cleavable complex between topoisomerase I and DNA (Hsiang et al., 1989;Schneider et al., 1990).,In past years, 9-nitro-20(S)-camptothecin (9NC), an analog of CPT, has been a focus of attention in cancer research and has been in early clinical trials (Verschraegen et al., 1998(Verschraegen et al., , 1999. Pharmacological studies have shown that the antitumor activity of 9NC is superior to the activity of CPT in human tumors xenografted in nude mice (Giovanella et al., 1991). 9NC is partially metabolized into 9-amino-20(S)-camptothecin (9AC) in vitro and in vivo (Peterslund and Boesen, 1994;Schoemaker et al., 2002). Pharmacokinetics of 9NC in dogs, mice, and humans have been reported, and the results of the studies on the conversion of 9NC to 9AC in different species were described (Hinz et al., 1994). In the present study, more metabolites of 9NC in rat bile, urine, and feces were identified after i.v. administration. Materials and MethodsChemicals and Drugs. 9-Nitro-20(S)-camptothecin was provided by Shenlong Biotechnology Co., Ltd. (Shanghai, China). 9-Amino-20(S)-camptothecin, 9-hydroxy-20(S)-camptothecin (9-OH-CPT), and 9-acetamido-20(S)-camptothecin (9-AA-CPT) were synthesized at the Department of Pharmaceutical Chemistry, Shenyang Pharmaceutical University (Shenyang, China). The purity of each of the synthesized compounds was checked by HPLC and was higher than 98%. All other chemicals and solvents were purchased from commercial sources and used as received.Chemical Syntheses. 9AC and 9-OH-CPT were synthesized using the published procedures as described below (Wall et al., 1993), and 9-AA-CPT was obtained according to the synthesis procedure of 9-acetamido-10-hydroxy-20(S)-camptothecin (Wani et al., 1986). Identity was confirmed by examining the mass spectra and NMR spectra.Synthesis of 9AC (M3 Reference). 9NC (0.20 g) was added to a cold (Ϫ12°C) stirred solution of anhydrous SnCl 2 (0.3 g) in concentrated HCl (3 ml). The bright yellow mixture was stirred at ambient temperature for 1.5 h, during which time a homogenous solution resulted, followed by another bright yellow suspension. The mixture was cooled to -12°C, and the solid was collected by filtration and washed with cold concentrated HCl (3 ml). The wet solid was dried at 60°C in vacuum for 3 h after washing with water (15 ml). Synthesis of 9-OH-CPT (M7 Reference).A cold (0 -5°C) stirred...

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“…Phase I metabolism is dominated by the microsomal mixed-function oxidase (MMFO) system and this is known to be involved both in the metabolism of endogenous compounds (steroid hormones, thyroid hormones, fatty acids, prostaglandins and derivatives) as well as in the biotransformation of drugs (or other xenobiotics) [6,8,17].…”

Section: Components Of the Enzyme System And Selected Miscellaneous Omentioning

confidence: 99%

“…Most frequently, these reactions are monooxygenation reactions (incorporating only one of the two atoms of molecular oxygen -see reaction below), the corresponding enzymes thus being categorised as monooxygenases [6,17].…”

Section: Components Of the Enzyme System And Selected Miscellaneous Omentioning

confidence: 99%