Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein (P-gp) expels various drugs from cells, resulting in multidrug resistance, including against glucocorticoids. Here, we present a case of systemic lupus erythematosus (SLE) that suggests the importance of initial intensive treatment in overcoming unresponsiveness due to P-gp overexpression on activated lymphocytes. A 28-year-old woman had been diagnosed with highly active SLE including severe pericarditis, hemolytic anemia, lupus nephritis, and retinopathy. The disease activity of SLE progressed despite 1 mg/kg per day oral prednisolone. At the time, P-gp expression was extremely high, as evaluated by flow cytometric analysis on peripheral lymphocytes. After intensive treatment with three courses of methylprednisolone pulse therapy and plasmapheresis, we succeeded in controlling disease activity in association with marked reduction of P-gp overexpression; namely, the clinical symptoms immediately improved along with the reduction of P-gp expression. These results imply that patients with highly active SLE might have drug unresponsiveness that is mediated by P-gp overexpression on lymphocytes. Therefore, downregulation of P-gp by initial intensive immunosuppressive therapy might be important for overcoming glucocorticoid resistance. We also propose that measurement of P-gp on lymphocytes is a useful test for prediction of drug resistance and may assist in the selection of appropriate initial treatment.
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PMID:Overcoming treatment unresponsiveness mediated by P-glycoprotein overexpression on lymphocytes in refractory active systemic lupus erythematosus. 1702 18

Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.
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PMID:A Review of Pharmacogenetics of Antimalarials and Associated Clinical Implications. 2807 Aug 79