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Titolo:
COMPARISON OF THE METABOLISM AND TOXICITY OF DAPSONE IN RAT, MOUSE AND MAN
Autore:
TINGLE MD; MAHMUD R; MAGGS JL; PIRMOHAMED M; PARK BK;
Indirizzi:
UNIV AUCKLAND,DEPT PHARMACOL,PRIVATE BAG 92019 AUCKLAND 1 NEW ZEALAND UNIV LIVERPOOL,DEPT PHARMACOL & THERAPEUT,ASHTON ST SCH MED LIVERPOOLL69 3GE MERSEYSIDE ENGLAND
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 2, volume: 283, anno: 1997,
pagine: 817 - 823
SICI:
0022-3565(1997)283:2<817:COTMAT>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED HEMOLYTIC-ANEMIA; IN-VITRO; HEMATOLOGICAL TOXICITY; HYDROXYLAMINE METABOLITES; N-HYDROXYLATION; DRUG-METABOLISM; INHIBITION; LIVER; DIPHENYLSULFONES; PHARMACOKINETICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
45
Recensione:
Indirizzi per estratti:
Citazione:
M.D. Tingle et al., "COMPARISON OF THE METABOLISM AND TOXICITY OF DAPSONE IN RAT, MOUSE AND MAN", The Journal of pharmacology and experimental therapeutics, 283(2), 1997, pp. 817-823

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 seenin 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, becausethe 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 14/07/20 alle ore 09:38:33