Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver

Platzer, Peter; Thalhammer, Theresia; Reznicek, Gottfried; Hamilton, Gerhard; Zhang, Ruiwen; Jäger, Walter

doi:10.3892/ijo.19.6.1287

Cited by 5 publications

(7 citation statements)

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“…Using a sensitive LC/MS/MS system we detected two phase I metabolites M1, dihydroxy-9-AC and M2, monohydroxy-9-AC, in both rat and human liver. Hepatic hydroxylation of 9-AC is in line with literature data as phase I biotransformation has already been reported as the major metabolic pathway for lipophilic camptothecin derivates, such as 10-hydroxycampto thecin (30), irinothecan (31) and topotecan (24). In contrast to other camptothecin derivates, 9-AC and its hydroxylation products did not undergo further phase II conjugation.…”

Section: Discussionsupporting

confidence: 78%

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Maier‐Salamon

Thalhammer

Reznicek

et al. 2014

International Journal of Oncology

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The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 (V(max)/K(m)) were 1.7- and 2.7‑fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.

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Section: Discussionsupporting

confidence: 78%

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Maier‐Salamon

Thalhammer

Reznicek

et al. 2014

International Journal of Oncology

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“…Moreover, Huang and Vore (2001) reported that bile flow in Abcb4 (Mdr2)Ϫ/Ϫ mice was higher than in wild-type mice in liver perfusion studies using the Abcc2 substrate estradiol-17␤-D-glucuronide. Bile flow in rats may be increased by solvent drag associated with concentrative excretion of drugs into bile (Platzer et al, 2001). In the current study, therefore, increased bile flow in Abcg2Ϫ/Ϫ mice may be attributed to elevated solvent drag caused by greater CDF biliary excretion.…”

Section: Discussionmentioning

confidence: 99%

ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN INAbcg2(Bcrp1) ANDAbcc2(Mrp2) KNOCKOUT MICE

Nezasa

Tian²,

Zamek‐Gliszczynski³

et al. 2006

Drug Metab Dispos

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ABSTRACT:This study characterized the hepatobiliary disposition of 5 (and 6)-carboxy-2,7-dichlorofluorescein (CDF), a model Abcc2/Mrp2 (canalicular) and Abcc3/Mrp3 (basolateral) substrate, in perfused livers from male C57BL/6 wild-type, Abcg2؊/؊, and Abcc2؊/؊ mice. After single-pass liver perfusion with 1 M CDF diacetate for 30 min and an additional 30-min perfusion with CDF-free buffer, cumulative biliary excretion of CDF in Abcg2؊/؊ mice was significantly higher than in wild-type mice (65 ؎ 6 and 47 ؎ 15% of dose, respectively, p < 0.05), whereas CDF recovery in bile of Abcc2؊/؊ mice was negligible. Cumulative recovery of CDF in perfusate was significantly higher in Abcc2؊/؊ (90 ؎ 8% of dose) relative to wild-type (

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“…As a matter of fact, all the camptothecin analogues including their in vivo metabolic products possess the structure feature required to be discriminated by the mechanistic pathway in Figure 1. [11][12][13]34,35 Therefore, the two forms of each camptothecin analogue and metabolic product can be differentiated by 62 Da loss in (-)-ESI-MS/MS. As to the metabolic products, other chemical alterations occur besides hydrolysis of the lactone ring.…”

Section: Resultsmentioning

confidence: 99%

Identifying Lactone Hydrolysis in Pharmaceuticals. A Tool for Metabolite Structural Characterization

Bandu

Desaire

2005

Anal. Chem.

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Methods to characterize metabolic transformations in a rapid and reliable fashion are required for facilitating the development of all new pharmaceuticals. One metabolic transformation, which is the focus of this study, is lactone hydrolysis. For pharmaceuticals containing lactones, hydrolysis occurs readily due to both enzymatic and nonenzymatic processes. Hydrolysis affects both the bioavailability and the efficacy of lactone-containing drugs and pro-drugs. To facilitate the characterization of lactones and their corresponding hydrolysis products, we have developed a mass spectrometric method that can readily discriminate between a lactone and its corresponding carboxylic acid, even when these changes are accompanied by other modifications that occur during metabolism. This method uses characteristic product ions in MS/MS experiments, and the trends described herein can be applied broadly to several types of lactones. To demonstrate the efficacy of this approach, two different lactones that had undergone multiple modifications were characterized, and in both cases, lactone hydrolysis was readily discernible, based on the MS/MS data.

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Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver

Cited by 5 publications

References 0 publications

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN INAbcg2(Bcrp1) ANDAbcc2(Mrp2) KNOCKOUT MICE

Identifying Lactone Hydrolysis in Pharmaceuticals. A Tool for Metabolite Structural Characterization

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