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Titolo:
EFFECT OF DISPOSITION OF MANNICH ANTIMALARIAL AGENTS ON THEIR PHARMACOLOGY AND TOXICOLOGY
Autore:
RUSCOE JE; TINGLE MD; ONEILL PM; WARD SA; PARK BK;
Indirizzi:
UNIV AUCKLAND,SCH MED & HLTH SCI,DEPT PHARMACOL & CLIN PHARMACOL,PRIVATE BAG 92019 AUCKLAND 1 NEW ZEALAND UNIV LIVERPOOL,DEPT PHARMACOL & THERAPEUT LIVERPOOL L69 3GE MERSEYSIDE ENGLAND
Titolo Testata:
Antimicrobial agents and chemotherapy
fascicolo: 9, volume: 42, anno: 1998,
pagine: 2410 - 2416
SICI:
0066-4804(1998)42:9<2410:EODOMA>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMODIUM-FALCIPARUM; AMODIAQUINE; PYRONARIDINE; MALARIA; DRUGS; CHLOROQUINE; RESISTANCE; AGRANULOCYTOSIS; BIOACTIVATION; CHEMOTHERAPY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
J.E. Ruscoe et al., "EFFECT OF DISPOSITION OF MANNICH ANTIMALARIAL AGENTS ON THEIR PHARMACOLOGY AND TOXICOLOGY", Antimicrobial agents and chemotherapy, 42(9), 1998, pp. 2410-2416

Abstract

The use of the antimalarial agent amodiaquine has been curtailed due to drug-induced idiosyncratic reactions. These have been attributed tothe formation of a protein-reactive quinoneimine species via oxidation of the l-aminophenol group, Therefore, the effects of chemical modifications on the disposition of amodiaquine in relation to its metabolism, distribution, and pharmacological activity have been investigated. The inclusion of a group at the C-5' position of amodiaquine reduced or eliminated bioactivation, as determined by glutathione conjugate formation in vivo. This can be seen in two series of C-5'-substituted compounds: the bis-Mannich antimalarial agents, including cycloquine andpyronaridine, and mono-Mannich antimalarial agents containing a 5'-chlorophenyl group (tebuquine and 5'-CIPAQ). Chemical substitution at the C-5' position also resulted in compounds which underwent slower elimination (<5% of the dose excreted into bile and urine, compared with 50% for amodiaquine) and increased levels of accumulation in tissue (10% of the dose in the liver at 48 h compared with 1% with amodiaquine). This may be due to an increase in either the lipophilicity or the basicity of the analogs and may reflect the lack of metabolic clearance for these compounds. The alteration in the disposition following the introduction of the C-5' substituent resulted in an increased duration of antimalarial activity in the mouse compared with that for amodiaquine. While this is desirable in the treatment of malaria, repeated administration for prophylaxis may induce toxicity through accumulation. Therefore, by simple chemical modification it is possible to block the bioactivation of amodiaquine while maintaining and in some cases extending the duration of antimalarial activity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 04:22:52