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Comparison of the metabolism and toxicity of dapsone in rat, mouse and man
M D Tingle1, R Mahmud, J L Maggs
1Department of Pharmacology and Therapeutics, The University of Liverpool, Ashton Street Medical School, Liverpool, L69 3GE, United Kingdom.
Abstract:
The metabolism and toxicity of dapsone was compared in vitro and in vivo in rat, mouse and man. Metabolism was assessed by high-pressure liquid chromatography-mass spectrometry and methemoglobin formation has been used as a toxic endpoint. The greatest toxicity in vitro was seen in microsomes prepared from male Wistar rats (36.6 +/- 1.5% methemoglobin), although toxicity was also seen in microsomes from the female rat (8.2 +/- 1.3%), male CD1 (4.2 +/- 1.6%) and human (10. 9 +/- 1.1%). The rank order of toxicity agreed with the formation of the hydroxylamine metabolite in vitro. All microsomes were also capable of catalyzing the reverse reaction, i.e., reduction of the hydroxylamine to dapsone. However, in vivo administration of dapsone resulted in significant (P < 0.05) methemoglobinemia only in male rats and humans. This species difference in the susceptibility to dapsone toxicity could not be attributed solely to the sensitivity of the target erythrocytes, because the order of sensitivity to dapsone hydroxylamine was human > mouse > rat. Analysis of bile and urine revealed the formation of dapsone hydroxylamine and its glucuronide in male rats and humans, but not in female rats or mice. This species difference in the metabolism and toxicity of dapsone has important implications in the safety evaluation of related compounds for man.
Insights
Dapsone toxicity varies by species due to differing metabolism. Male rats and humans showed significant methemoglobinemia, impacting drug safety evaluations for related compounds.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Dapsone is a medication used to treat leprosy and certain skin conditions.
- Understanding dapsone's metabolism and toxicity is crucial for safe drug development.
- Species-specific differences in drug response can impact human safety assessments.
Purpose of the Study:
- To compare the in vitro and in vivo metabolism and toxicity of dapsone across different species (rat, mouse, human).
- To investigate the role of the hydroxylamine metabolite in dapsone-induced toxicity.
- To elucidate the reasons for observed species-specific differences in dapsone toxicity.
Main Methods:
- In vitro metabolism studies using liver microsomes from male/female rats, mice, and humans.
- Assessment of methemoglobin formation as a toxic endpoint.
- High-pressure liquid chromatography-mass spectrometry (HPLC-MS) for metabolite identification.
- In vivo studies involving dapsone administration and analysis of biological samples (bile, urine).
Main Results:
- In vitro, male Wistar rat microsomes exhibited the highest toxicity, followed by human, female rat, and mouse microsomes.
- In vivo, only male rats and humans developed significant methemoglobinemia after dapsone administration.
- Dapsone hydroxylamine formation correlated with toxicity in vitro; however, erythrocyte sensitivity order was human > mouse > rat.
- Dapsone hydroxylamine and its glucuronide were detected in male rats and humans, but not in female rats or mice.
Conclusions:
- Significant species-specific differences exist in dapsone metabolism and toxicity.
- Metabolism to dapsone hydroxylamine and subsequent excretion pathways contribute to these differences.
- Findings have critical implications for the safety evaluation of dapsone and related compounds in humans.