ABSTRACT
OBJECTIVE: The study was designed to evaluate the effect of hormone therapy (HT) preparations containing 17beta-estradiol and micronized progesterone administered orally and transdermally on the pharmacokinetics of lidocaine, a probe drug that is metabolized by liver oxidative pathways involving cytochrome P-450 1A2 and 3A4 (CYP1A2 and CYP3A4). DESIGN: The study was carried out in 18 postmenopausal women divided into two groups administered HT for 6 months: group 1, 17beta-estradiol (orally) and micronized progesterone sublingually; and group 2, 17beta-estradiol (transdermally) and micronized progesterone sublingually. Pharmacokinetic study with intravenous lidocaine (1 mg/kg) and blood sampling during 360 minutes from injection was performed before the HT initiation and after 3 and 6 months of HT. RESULTS: Pharmacokinetic parameters of lidocaine demonstrated accelerated drug elimination in women on oral HT after 3 months. A significant reduction of area under the curve by 15.0% (P < 0.05), shortening of t(1/2) by 15.2% (P < 0.05), increase of lambda(z) by 10.0% (P < 0.05), and Cl/BW by 14.3% (P < 0.05) were observed. In contrast, transdermal administration of HT did not influence pharmacokinetic parameters of the drug. The effects of oral HT were not seen 6 months after the start of HT. CONCLUSION: HT can influence the pharmacokinetics of lidocaine, ie, its hepatic metabolism, through CYP3A4 and CYP1A2. The effect depends on the route of administration and therapy duration.
Subject(s)
Anesthetics, Local/pharmacokinetics , Estradiol/metabolism , Hormone Replacement Therapy/adverse effects , Lidocaine/pharmacokinetics , Postmenopause/metabolism , Progesterone/metabolism , Administration, Cutaneous , Administration, Sublingual , Area Under Curve , Cytochrome P-450 CYP1A2/blood , Cytochrome P-450 CYP1A2/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/blood , Cytochrome P-450 Enzyme System/drug effects , Estradiol/administration & dosage , Female , Humans , Liver/drug effects , Liver/metabolism , Middle Aged , Postmenopause/drug effects , Progesterone/administration & dosage , Regression Analysis , Time FactorsABSTRACT
Insulin deficiency can trigger not only an altered glucose metabolic state but may also affect drug metabolism. The formation rate of the major lidocaine metabolite monoethylglycinxylidide (MEGX) has been shown to reflect the activity of CYP3A2 and CYP1A2. In the present study the effects of streptozotocin-induced diabetes on lidocaine elimination and MEGX formation in a model of isolated, non-recirculated, perfused rat liver with constant flow was evaluated. The parameters describing hepatic lidocaine elimination studied 10 days after streptozotocin administration, i.e. hepatic extraction coefficient (E(H)), hepatic clearance (Cl(H)) and elimination rate (V(L)), were significantly decreased in diabetic livers in comparison with the controls. The E(H) in the controls varied between 0.88+/-0.07 and 0.93+/-0.06, whereas in diabetic livers it was markedly reduced to between 0.27+/-0.15 and 0.39+/-0.23. The Cl(H) dropped to 8.04+/-4.12 - 11.66+/-2.99 mL min(-1) in diabetic rats in comparison to 26.29+/-2.07 - 27.94+/-0.92 mL min(-1) in the control animals. The V(L) was estimated to be 128.08+/-18.60 - 136.44+/-17.59 microg mL(-1) in the controls and from 40.87+/-28.31 microg mL(-1) to 56.83+/-22.16 microg mL(-1) in diabetic perfused livers. The major lidocaine metabolite, i.e. MEGX, concentrations were significantly decreased in diabetic rats compared to the controls. The observed changes indicate an impairment of N-deethylation metabolic pathway in streptozotocin-induced diabetic rats, i.e. a possible decrease in the enzymatic activity of CYP3A2 and CYP1A2.
Subject(s)
Anesthetics, Local/metabolism , Diabetes Mellitus, Experimental/metabolism , Lidocaine/metabolism , Liver/metabolism , Animals , Body Weight/physiology , In Vitro Techniques , Lidocaine/analogs & derivatives , Rats , Rats, WistarABSTRACT
O objetivo da experiencia foi determinar o efeito da hiperlipidemia experimental na farmacocinetica da procainamida (PA) e N-acetilprocainamida (NAPA), cujo nome oficial e acecainida. A experiencia foi realizada em um periodo de dois meses em 20 coelhos, machos, divididos aleatoriamente em dois grupos: controle e experimental (deixado em dieta rica em gorduras). Depois dos dois meses foram realizadas determinacoes farmacocineticas em todos os animais. Apos administracao estomacal (por sonda) de procainamida em dose de 40 mg/kg, foi coletado sangue para as determinacoes, durante um periodo de 12 horas. Para calculos, foi tomado o modelo de dois compartimentos para administracao extravascular. Foi observada diminuicao da concentracao da PA e NAPA no sangue, diminuicao do volume de distribuicao e aumento da depuracao total. A presente experiencia demonstrou o efeito da hiperlipidemia experimental na farmacocinetica de PA e NAPA, seguido de aumento da velocidade de eliminacao do farmaco do organismo
Subject(s)
Animals , Male , Infant , Rabbits , Hyperlipidemias/metabolism , Procainamide/blood , Procainamide/pharmacokinetics , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/blood , Drug Administration RoutesABSTRACT
A zopiclona é a primeira das ciclospirinas, nova classe de agentes psicoterápicos. Possui perfil farmacológico de alta eficácia de baixa toxicidade. Liga-se a receptores específicos do Gaba (canal de cloreto e sítios alostéricos benzodiazepínicos). Embora a zopiclona manifeste atividade anticonvulsionante, miorrelaxante e ansiolítica, o principal uso é hipnótico, devido ao efeito sedativo
