This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hande, K. Articles by Branch, R. Search for Related Content PubMed PubMed Citation Articles by Hande, K. Articles by Branch, R.

Identification of Etoposide Glucuronide as a Major Metabolite of Etoposide in the Rat and Rabbit¹

Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine and the Nashville Veterans Administration Medical Center, Nashville, Tennessee 37232

Isolated livers from male Sprague-Dawley rats were perfused at 20 ml/min for 3 h at 37°C with 100 ml of an oxygenated, recirculating solution of 20% rat blood in Krebs bicarbonate buffer containing 20 µg/ml [³H]etoposide. Ninety % of administered radioactivity was eliminated in bile over a 3-h collection period. The clearance of etoposide was 3.56 ml/min indicating that, in the rat, it is not highly extracted. Its clearance is, therefore, independent of hepatic blood flow. Etoposide was both excreted into the bile and metabolized by the liver. Perfusate and bile samples analyzed by reverse-phase high-performance liquid chromatography techniques were found to contain three peaks of radioactivity. Positive and negative ion fast atom bombardment mass spectrometry identified the first two peaks as etoposide glucuronides and the third peak as parent drug. Following the i.v. administration of etoposide to rabbits, etoposide glucuronide was also identified in rabbit urine. The recovery of etoposide both from rabbit urine and rat bile was increased by preincubation with glucuronidase. However, the glucuronides were relatively resistant to the action of glucuronidase and showed varying sensitivity to the type of glucuronidase and the reaction conditions used. These studies document the presence of etoposide glucuronide as an etoposide metabolite in two mammalian species and suggest that previous clinical studies using ß-glucuronidase to quantitate glucuronide formation may have underestimated this metabolite due to its relative resistance to some glucuronidase preparations.

¹ Supported by United States Public Health Service Grants CA39686, GM31304, and RR01688, and by the Veterans Administration.

² To whom correspondence should be addressed, at A2127 Medical Center North, Vanderbilt University, Nashville, TN 37232.

Received 8/26/87. Revised 12/22/87. Accepted 1/ 6/88.

This article has been cited by other articles:

				Z. Wen, M. N. Tallman, S. Y. Ali, and P. C. Smith UDP-Glucuronosyltransferase 1A1 Is the Principal Enzyme Responsible for Etoposide Glucuronidation in Human Liver and Intestinal Microsomes: Structural Characterization of Phenolic and Alcoholic Glucuronides of Etoposide and Estimation of Enzyme Kinetics Drug Metab. Dispos., March 1, 2007; 35(3): 371 - 380. [Abstract] [Full Text] [PDF]

				Y. Watanabe, M. Nakajima, N. Ohashi, T. Kume, and T. Yokoi Glucuronidation of Etoposide in Human Liver Microsomes Is Specifically Catalyzed by UDP-Glucuronosyltransferase 1A1 Drug Metab. Dispos., May 1, 2003; 31(5): 589 - 595. [Abstract] [Full Text] [PDF]

				N. Zelcer, T. Saeki, G. Reid, J. H. Beijnen, and P. Borst Characterization of Drug Transport by the Human Multidrug Resistance Protein 3 (ABCC3) J. Biol. Chem., November 30, 2001; 276(49): 46400 - 46407. [Abstract] [Full Text] [PDF]

				K. Hande, M. Messenger, J. Wagner, M. Krozely, and S. Kaul Inter- and Intrapatient Variability in Etoposide Kinetics with Oral and Intravenous Drug Administration Clin. Cancer Res., October 1, 1999; 5(10): 2742 - 2747. [Abstract] [Full Text] [PDF]

				D. E. Burgio, M. P. Gosl, and a. P. J. McNamara Effects of P-glycoprotein Modulators on Etoposide Elimination and Central Nervous System Distribution J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 911 - 917. [Abstract] [Full Text]

				D. W. Loe, K. C. Almquist, S. P. C. Cole, and R. G. Deeley ATP-dependent 17beta-Estradiol 17-(beta-D-Glucuronide) Transport by Multidrug Resistance Protein (MRP) J. Biol. Chem., April 19, 1996; 271(16): 9683 - 9689. [Abstract] [Full Text] [PDF]