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Metabolism and elimination of rhodamine 123 in the rat

  • Original Articles
  • Rhodamine 123, Pharmacokinetics
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Summary

Little is known of the pharmacology of rhodamine 123 (RH-123), an agent reported to have carcinoma-selective experimental antitumor activity. Accordingly, using a high-performance liquid chromatographic assay system with fluorescence detection, we examined the plasma decay and the biliary and urinary elimination of parent drug and metabolites in female Sprague-Dawley rats receiving RH-123 at an intravenous dose (5 mg/kg) equivalent to the therapeutic dose used in murine tumor models. Following drug administration to unconscious animals, plasma levels of drug-associated fluorescence fell in a triphasic manner (t1/2α, 15 min; t1/2β, 1 h; t1/2γ, 4.7 h). In plasma, unchanged drug predominated but lower levels of the deacylated metabolite rhodamine 110 (RH-110) and two unknowns were also detectable throughout the study. Drug fluorescence was recovered extensively in both urine and bile. In unconscious animals with ureteral cannulae, urinary excretion (11.4% of the dose in 6 h) occurred predominantly as unchanged RH-123 (97% of the total), with low levels of RH-110 (2.4%) and two unknowns (<0.6% combined) also being present. Similarly dosed conscious animals (without surgical intervention) housed in metabolic cages showed a comparable pattern of urinary excretion, with 11.9% of the drug dose being recovered in 6 h and 21.9%, by 48 h. Biliary drug elimination accounted for 8% of the delivered dose in 6 h in unconscious animals and for 11% by 36 h in conscious animals fitted with biliary cannulae. In contrast to urinary excretion, in which unchanged drug predominated, only 50% of the fluorescence recovered in bile was attributable to RH-123. The remainder was due to a number of products that were detectable throughout the study. Of these, one present at significant levels was identified as a glucuronide conjugate of RH-123, based on the liberation of parent drug when the purified metabolite was incubated with β-glucuronidase or hydrolyzed with 1 N hydrochloric acid. Further studies with a radiolabeled form of RH-123 are necessary to establish the identity of the remaining unknowns disclosed in this work.

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This work was supported in part by research grants CA 44890 (T.W.S.) and CA 37082 (M.I.) from the National Cancer Institute, National Institutes of Health, United States Public Health Service

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Sweatman, T.W., Seshadri, R. & Israel, M. Metabolism and elimination of rhodamine 123 in the rat. Cancer Chemother. Pharmacol. 27, 205–210 (1990). https://doi.org/10.1007/BF00685714

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