Toxicological implications of hepatobiliary transporters

Kato, Yukio; Suzuki, Hiroshi; Sugiyama, Yuichi

doi:10.1016/s0300-483x(02)00458-4

Cited by 29 publications

(16 citation statements)

References 6 publications

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“…Interestingly, the majority of exisulind undergoes biliary excretion with no evidence of metabolism by the cytochrome P450 isoenzyme system, which can be a major source of interpatient variability (19,26). Thus, the etiology of this variability may be related to hepatobiliary transporters that have also been implicated in the gastrointestinal toxic effects of a range of agents including NSAIDS, irinotecan, and methotrexate (27,28). By contrast, the mean C max concentrations of docetaxel achieved at the 30 and 36 mg/m 2 dose levels ranged from 67 to 1,278 nmol/L, which was significantly higher than the IC 50 (2.5 nmol/L) reported in the preclinical studies of docetaxel and exisulind against the A549 NSCLC cell line (16).…”

Section: Discussionmentioning

confidence: 99%

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

Witta¹,

Gustafson²,

Pierson³

et al. 2004

Clinical Cancer Research

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Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study.Experimental Design: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150 -250 mg) given orally twice daily and docetaxel (30 -36 mg/m 2 ) administered intravenously on days 1, 8, and 15 of a 4-week cycle.Results: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35-77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m 2 . Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed.Conclusions: The combination of docetaxel (36 mg/m 2 , weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non-small-cell lung cancer.

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Section: Discussionmentioning

confidence: 99%

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

Witta¹,

Gustafson²,

Pierson³

et al. 2004

Clinical Cancer Research

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“…Hepatocytes are a widely accepted in vitro tool for evaluating mechanisms of hepatic uptake and metabolism of xenobiotics and hepatotoxicity (Iwatsubo et al, 1997;Kato et al, 2002;Hirano et al, 2005). However, it was reported that cell polarity and liver-specific functions, such as albumin secretion, hepatic uptake, and enzyme activity under conventional monolayer culture conditions were rapidly lost (Foliot et al, 1985;Dunn et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

Nakakariya

Ono²,

Amano³

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:It has been reported that in vivo biliary clearance can be predicted using sandwich-cultured rat and human hepatocytes. The predicted apparent biliary clearance (CL bile, app ) from sandwichcultured rat hepatocytes (SCRH) based on medium concentrations correlates to in vivo CL bile, app based on plasma concentrations of angiotensin II receptor blockers (ARBs), HMG-CoA reductase inhibitors (statins), ␤-lactam antibiotics, and topotecan. However, the predicted biliary clearance from SCRH was 7-to 300-fold lower than in vivo biliary clearance. We speculated that the process of biliary excretion might not have been evaluated using sandwichcultured hepatocytes. To evaluate this issue, intrinsic biliary clearance (CL bile, int ) based on intracellular compound concentrations was evaluated to investigate the in vitro-in vivo correlation of this process among ARBs, statins, ␤-lactam antibiotics, and topotecan. Intrinsic biliary clearance in SCRH correlated to in vivo values obtained by constant intravenous infusion of six compounds, but not rosuvastatin and cefmetazole, to rats. Moreover, differences between SCRH and in vivo CL bile, int (0.7-6-fold) were much smaller than those of CL bile, app (7-300-fold). Therefore, in vivo CL bile, int is more accurately reflected using SCRH than CL bile, app . In conclusion, to predict in vivo biliary clearance more accurately, CL bile, int should be evaluated instead of CL bile, app between SCRH and in vivo.

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“…In rats, pravastatin and methotrexate were minimally metabolized and were primarily excreted intact into bile (Masuda et al, 1997;Kurihara et al, 2005). Extensive biliary excretion can be linked to a high clearance (Arimori et al, 2003), enterohepatic recirculation (Caldwell and Cline 1976;Rollins and Klaassen 1979), toxic gastrointestinal side effects (Kato et al, 2002), and potential drug-drug interactions (Luo et al, 2007). As a result, most lead discovery compounds are assessed for biliary excretion in selected preclinical animals early in the drug discovery and development process.…”

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confidence: 99%

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Luo¹,

Johnson²,

Hsueh³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile ductcannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time-consuming and cost-ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol-Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at <10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r ‫؍‬ 0.76) and with free energy of aqueous solvation (⌬G solv aq ) (r ‫؍‬ ؊0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r ‫؍‬ 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r ‫؍‬ 0.94) and for 25 previously reported compounds (r ‫؍‬ 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.Biliary excretion is a major elimination pathway for many drugs and discovery compounds both in humans and in preclinical animals. For example, pravastatin and losoxantrone were found to be mainly eliminated as intact parent through biliary excretion in humans (Hatanaka 2000;Joshi et al., 2001). In rats, pravastatin and methotrexate were minimally metabolized and were primarily excreted intact into bile (Masuda et al., 1997;Kurihara et al., 2005). Extensive biliary excretion can be linked to a high clearance (Arimori et al., 2003), enterohepatic recirculation (Caldwell and Cline 1976;Rollins and Klaassen 1979), toxic gastrointestinal side effects (Kato et al., 2002), and potential drug-drug interactions (Luo et al., 2007). As a result, most lead discovery compounds are assessed for biliary excretion in selected preclinical animals early in the drug discovery and development process.Among the preclinical animal models, rats are the most commonly used model species for pharmacology, pharmacokinetics, and toxicology. The existing experimental models for determining rat biliary excretion include bile duct-cannulated rats and isolated perfused rat liver. However, these models are very time-consuming and costineffective because of complicated preparation of test models and difficulty in bile sample analyses.Undoubtedly, a computational model for predicting rat biliary excretion could significantly reduce laboratory efforts and, consequently, cost. Furthermore, a...

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Toxicological implications of hepatobiliary transporters

Cited by 29 publications

References 6 publications

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

A Phase I and Pharmacokinetic Study of Exisulind and Docetaxel in Patients with Advanced Solid Tumors

In Vivo Biliary Clearance Should Be Predicted by Intrinsic Biliary Clearance in Sandwich-Cultured Hepatocytes

In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

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