Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat

R. W. Klecker, Carlos Alberto Jamis-Dow, M. J. Egorin, K. Erkmen, R. J. Parker, R. Stevens, J. M. Collins

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Abstract

Male Sprague-Dawley rats had their bile ducts cannulated and were dosed with [3H]taxol (2 mg/kg, 68-77 μCi/mg) as a continuous intravenous infusion for 6 hr so that the plasma concentrations, tissue distribution, metabolism, and biliary secretion of taxol could be studied. Defining potential drug- drug interactions of taxol with cimetidine (90 mg/kg), probenecid (360 mg/kg), and ketoconazole (50 mg/kg) was motivated by frequent concomitant clinical use or the potential to reduce clearance of taxol so that lower doses could be used. At 6 hr, rats were killed. Samples of blood (plasma), lung, spleen, liver, kidney, heart, skeletal muscle, brain, testes, and fat were obtained. Taxol and metabolites were measured by total radioactivity counting and HPLC separation using on-line radioactivity detection. Concentrations of taxol in plasma increased to 0.19 μM in the control rats and did not reach steady-state by 6 hr. Lung, spleen, liver, and kidneys had the greatest tissue taxol concentrations [4.7-5.7 nmol/g (μM)] and were >25- fold higher than the simultaneous 6-hr plasma taxol concentration. Taxol concentrations in brain and testes were negligible, 0.06 and 0.07 nmol/g, respectively. Radioactive metabolites were not found in plasma or most tissues. Only liver had appreciable concentrations of taxol and metabolites; however, >80% of hepatic radioactivity was parent taxol. Through 6 hr of collection, 24% of the dose was secreted in the bile ~38% of which was as parent taxol. Cimetidine had no effect on the distribution, metabolism, or elimination of [3H]taxol. Probenecid did not effect tissue distribution or plasma concentrations of taxol. Probenecid decreased the biliary secretion of taxol and metabolites by 50%. Rats pretreated with ketoconazole had biliary secretion of taxol, and metabolites decreased to 25% of control with a concomitant increase in plasma taxol concentration.

Original languageEnglish (US)
Pages (from-to)254-258
Number of pages5
JournalDrug Metabolism and Disposition
Volume22
Issue number2
StatePublished - Apr 5 1994

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Probenecid
Ketoconazole
Cimetidine
Paclitaxel
Sprague Dawley Rats
Radioactivity
Liver
Tissue Distribution
Testis
Spleen
Kidney
Lung

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Klecker, R. W., Jamis-Dow, C. A., Egorin, M. J., Erkmen, K., Parker, R. J., Stevens, R., & Collins, J. M. (1994). Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat. Drug Metabolism and Disposition, 22(2), 254-258.
Klecker, R. W. ; Jamis-Dow, Carlos Alberto ; Egorin, M. J. ; Erkmen, K. ; Parker, R. J. ; Stevens, R. ; Collins, J. M. / Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat. In: Drug Metabolism and Disposition. 1994 ; Vol. 22, No. 2. pp. 254-258.
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abstract = "Male Sprague-Dawley rats had their bile ducts cannulated and were dosed with [3H]taxol (2 mg/kg, 68-77 μCi/mg) as a continuous intravenous infusion for 6 hr so that the plasma concentrations, tissue distribution, metabolism, and biliary secretion of taxol could be studied. Defining potential drug- drug interactions of taxol with cimetidine (90 mg/kg), probenecid (360 mg/kg), and ketoconazole (50 mg/kg) was motivated by frequent concomitant clinical use or the potential to reduce clearance of taxol so that lower doses could be used. At 6 hr, rats were killed. Samples of blood (plasma), lung, spleen, liver, kidney, heart, skeletal muscle, brain, testes, and fat were obtained. Taxol and metabolites were measured by total radioactivity counting and HPLC separation using on-line radioactivity detection. Concentrations of taxol in plasma increased to 0.19 μM in the control rats and did not reach steady-state by 6 hr. Lung, spleen, liver, and kidneys had the greatest tissue taxol concentrations [4.7-5.7 nmol/g (μM)] and were >25- fold higher than the simultaneous 6-hr plasma taxol concentration. Taxol concentrations in brain and testes were negligible, 0.06 and 0.07 nmol/g, respectively. Radioactive metabolites were not found in plasma or most tissues. Only liver had appreciable concentrations of taxol and metabolites; however, >80{\%} of hepatic radioactivity was parent taxol. Through 6 hr of collection, 24{\%} of the dose was secreted in the bile ~38{\%} of which was as parent taxol. Cimetidine had no effect on the distribution, metabolism, or elimination of [3H]taxol. Probenecid did not effect tissue distribution or plasma concentrations of taxol. Probenecid decreased the biliary secretion of taxol and metabolites by 50{\%}. Rats pretreated with ketoconazole had biliary secretion of taxol, and metabolites decreased to 25{\%} of control with a concomitant increase in plasma taxol concentration.",
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Klecker, RW, Jamis-Dow, CA, Egorin, MJ, Erkmen, K, Parker, RJ, Stevens, R & Collins, JM 1994, 'Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat', Drug Metabolism and Disposition, vol. 22, no. 2, pp. 254-258.

Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat. / Klecker, R. W.; Jamis-Dow, Carlos Alberto; Egorin, M. J.; Erkmen, K.; Parker, R. J.; Stevens, R.; Collins, J. M.

In: Drug Metabolism and Disposition, Vol. 22, No. 2, 05.04.1994, p. 254-258.

Research output: Contribution to journalArticle

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T1 - Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat

AU - Klecker, R. W.

AU - Jamis-Dow, Carlos Alberto

AU - Egorin, M. J.

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AU - Parker, R. J.

AU - Stevens, R.

AU - Collins, J. M.

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