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
The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Alimentos , Hipoglicemiantes/farmacologia , Plantas/metabolismo , Resveratrol/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Disponibilidade Biológica , Biotransformação , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/toxicidade , Vias de Eliminação de Fármacos , Absorção Gastrointestinal , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Isomerismo , Resveratrol/metabolismo , Resveratrol/farmacocinética , Resveratrol/toxicidadeRESUMO
The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ngâ h/mL (927 to 2531 ngâ h/mL); AUC0-∞ , 1580 ngâ h/mL (1270 to 2881 ngâ h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.
Assuntos
Líquido Amniótico/metabolismo , Diuréticos/farmacocinética , Furosemida/farmacocinética , Hipertensão Induzida pela Gravidez , Hipertensão/tratamento farmacológico , Troca Materno-Fetal/fisiologia , Administração Oral , Adulto , Cesárea , Diuréticos/administração & dosagem , Diuréticos/sangue , Diuréticos/urina , Cálculos da Dosagem de Medicamento , Vias de Eliminação de Fármacos , Feminino , Sangue Fetal/metabolismo , Furosemida/administração & dosagem , Furosemida/sangue , Furosemida/urina , Glucuronosiltransferase/metabolismo , Humanos , Hipertensão/sangue , Hipertensão/urina , Parto/sangue , Parto/urina , Projetos Piloto , GravidezRESUMO
The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CLCR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 × (CLCR/130)0.84 and V (liters) = 20.3 × (IBW/68)2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, -3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CLCR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.