RESUMO
BACKGROUND: Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions. OBJECTIVE: In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans. RESULTS: An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals. CONCLUSION: Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.
Assuntos
Antimaláricos/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Vias de Eliminação de Fármacos , Malária , Animais , Humanos , Inativação Metabólica , Malária/tratamento farmacológico , Malária/metabolismo , Taxa de Depuração Metabólica , RoedoresRESUMO
A series of experiments were conducted to investigate the effect of rutting season on metabolism of testosterone (T) and its effect on drug metabolizing enzymes in dromedary camels. Serum and tissue samples were collected from liver, testes and poll glands of rutting and non- rutting camels treated with T at a dose of 0.5 mg/kg or 5α-dihydrotestosterone (DHT) at a dose of 0.2 mg/kg, given intramuscularly for 7 days. Liver samples were also used to monitor drug metabolizing enzymes. Testosterone and DHT concentrations were significantly (P<0.05) increased in testicular tissue and peripheral circulation of rutting camels compared to non-rutting camels and in non-rutting camels treated with T or DHT. Drug metabolizing enzymes of phase-1 reaction were significantly (P<0.05) inhibited in livers of rutting camels and in non-rutting camels treated with T and DHT. It is suggested that co-administration of drugs metabolized by oxidation with androgens should be avoided. Such drugs may cause adverse drug reaction in rutting camels.
RESUMO
Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach the fruitful results. There are many causes for this resistance that are being studied by the researchers across the world, but still, success is far because there are several factors that are going along unattended or have been studied less. Drug-metabolizing enzymes (DMEs) are one of these factors, on which less study has been conducted. DMEs include Phase I and Phase II enzymes. Cytochrome P450s (CYPs) are major Phase I enzymes while glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), dihydropyrimidine dehydrogenases are the major enzymes belonging to the Phase II enzymes. These enzymes play an important role in detoxification of the xenobiotics as well as the metabolism of drugs, depending upon the tissue in which they are expressed. When present in tumorous tissues, they cause resistance by metabolizing the drugs and rendering them inactive. In this review, the role of these various enzymes in anticancer drug metabolism and the possibilities for overcoming the resistance have been discussed.
Assuntos
Antineoplásicos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Catálise , Sistema Enzimático do Citocromo P-450/fisiologia , Di-Hidrouracila Desidrogenase (NADP)/fisiologia , Glucuronosiltransferase/fisiologia , Glutationa Transferase/fisiologia , Humanos , Inativação MetabólicaRESUMO
A series of experiments were conducted to investigate the effect of rutting season on metabolism of testosterone (T) and its effect on drug metabolizing enzymes in dromedary camels. Serum and tissue samples were collected from liver, testes and poll glands of rutting and non- rutting camels treated with T at a dose of 0.5 mg/kg or 5α-dihydrotestosterone (DHT) at a dose of 0.2 mg/kg, given intramuscularly for 7 days. Liver samples were also used to monitor drug metabolizing enzymes. Testosterone and DHT concentrations were significantly (P<0.05) increased in testicular tissue and peripheral circulation of rutting camels compared to non-rutting camels and in non-rutting camels treated with T or DHT. Drug metabolizing enzymes of phase-1 reaction were significantly (P<0.05) inhibited in livers of rutting camels and in non-rutting camels treated with T and DHT. It is suggested that co-administration of drugs metabolized by oxidation with androgens should be avoided. Such drugs may cause adverse drug reaction in rutting camels.
Assuntos
Animais , Androgênios/análise , Androgênios/efeitos adversos , Camelus/metabolismo , Comportamento Sexual AnimalRESUMO
A series of experiments were conducted to investigate the effect of rutting season on metabolism of testosterone (T) and its effect on drug metabolizing enzymes in dromedary camels. Serum and tissue samples were collected from liver, testes and poll glands of rutting and non- rutting camels treated with T at a dose of 0.5 mg/kg or 5α-dihydrotestosterone (DHT) at a dose of 0.2 mg/kg, given intramuscularly for 7 days. Liver samples were also used to monitor drug metabolizing enzymes. Testosterone and DHT concentrations were significantly (P<0.05) increased in testicular tissue and peripheral circulation of rutting camels compared to non-rutting camels and in non-rutting camels treated with T or DHT. Drug metabolizing enzymes of phase-1 reaction were significantly (P<0.05) inhibited in livers of rutting camels and in non-rutting camels treated with T and DHT. It is suggested that co-administration of drugs metabolized by oxidation with androgens should be avoided. Such drugs may cause adverse drug reaction in rutting camels.(AU)