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1.
Biomolecules ; 13(6)2023 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-37371585

RESUMO

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the ß2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that ß2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by ß2 receptors is unable to provide meaningful tocolysis. The failure of ß2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The ß3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of ß2 agonists as tocolytics and suggests a non-canonical signaling role for ß3AR in myometrium. The addition of the ß3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to ß3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth.


Assuntos
Trabalho de Parto Prematuro , Nascimento Prematuro , Tocolíticos , Recém-Nascido , Gravidez , Feminino , Humanos , Miométrio/metabolismo , Tocolíticos/farmacologia , Tocolíticos/metabolismo , Tocolíticos/uso terapêutico , Nascimento Prematuro/prevenção & controle , Óxido Nítrico/metabolismo , Células Endoteliais/metabolismo , Trabalho de Parto Prematuro/tratamento farmacológico , Trabalho de Parto Prematuro/prevenção & controle , Trabalho de Parto Prematuro/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Receptores Adrenérgicos/metabolismo
2.
Semin Perinatol ; 38(8): 534-40, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25282474

RESUMO

Personalized medicine seeks to identify the right dose of the right drug for the right patient at the right time. Typically, individualization of therapy is based on the pharmacogenomic makeup of the individual and environmental factors that alter drug disposition and response. In addition to these factors, during pregnancy, a woman's body undergoes many changes that can impact the therapeutic efficacy of medications. Yet, there is minimal research regarding personalized medicine in obstetrics. Adoption of pharmacogenetic testing into the obstetrical care is dependent on evidence of analytical validity, clinical validity, and clinical utility. Here, we briefly present information regarding the potential utility of personalized medicine for treating the obstetric patient for pain with narcotics, hypertension, and preterm labor, and discuss the impediments of bringing personalized medicine to the obstetrical clinic.


Assuntos
Obstetrícia , Farmacogenética , Medicina de Precisão , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Entorpecentes/metabolismo , Entorpecentes/uso terapêutico , Trabalho de Parto Prematuro/tratamento farmacológico , Dor/tratamento farmacológico , Gravidez , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Tocolíticos/metabolismo , Tocolíticos/uso terapêutico
3.
J Matern Fetal Neonatal Med ; 25(4): 419-23, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21644845

RESUMO

OBJECTIVE: To characterize the pharmacokinetics of nifedipine when used for tocolysis in preterm labor and to determine the impact of genetics on these parameters. STUDY DESIGN: Pharmacokinetic study performed on women given tocolytic nifedipine. Over one dosing interval, drug concentrations, clinical data, and genotype for Cytochrome P450 (CYP)3A5 polymorphisms were obtained. Non-compartmental pharmacokinetic analysis was used to estimate nifedipine exposure at steady state. RESULTS: The mean nifedipine area under the curve in 20 pregnant women was 86.1±61.1 ng/ml/h. The mean nifedipine exposure differed by expression of CYP3A5 (expressers [exp]: 139.5±97.3 ng/ml/h vs. nonexpressers[non]: 68.3 ± 31.8 ng/ml/h, p = 0.02). Four women consumed CYP3A inhibitors and this affected the nifedipine concentrations (p < 0.001). CYP3A5 expressers had less improvement in contraction frequency after the loading dose (p = 0.04), at steady state (p = 0.006), and at 0-1 h after the study dose (p < 0.001). CONCLUSIONS: CYP3A5 genotype plays a role in nifedipine concentration when used as a tocolytic.


Assuntos
Citocromo P-450 CYP3A/genética , Nifedipino/farmacocinética , Trabalho de Parto Prematuro/tratamento farmacológico , Trabalho de Parto Prematuro/genética , Adolescente , Adulto , Citocromo P-450 CYP3A/fisiologia , Relação Dose-Resposta a Droga , Feminino , Genótipo , Meia-Vida , Humanos , Nifedipino/administração & dosagem , Nifedipino/metabolismo , Trabalho de Parto Prematuro/sangue , Oxirredução , Projetos Piloto , Gravidez , Tocolíticos/administração & dosagem , Tocolíticos/metabolismo , Tocolíticos/farmacocinética , Adulto Jovem
4.
Med Hypotheses ; 74(1): 81-2, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19692183

RESUMO

Leptin - a protein hormone is synthesised in the adipose tissue in humans. Its level therefore should be directly proportional to the amount of adipose tissue in the body. When biopsies of human myometrium from obese women were exposed to leptin, it showed a cumulative inhibitory effect on spontaneous as well as induced contractions. This lead to the proposed theory that leptin may be the cause of dysfunctional labour in obese women leading to increased caesarean section rates. There is an increased rate of post-dated pregnancies in obese women when compared to normal weight women with a consequent increased induction rate in women with a raised body mass index (BMI). Likewise there a decrease in the rate of spontaneous preterm delivery in obese women. These findings suggest that leptin inhibits uterine contractions in these women and this effect could be considered a tocolytic effect on uterine muscle. So could this hormone (leptin) be used as a tocolytic agent for threatened preterm labour in the future?


Assuntos
Leptina/fisiologia , Tocolíticos/metabolismo , Tecido Adiposo/metabolismo , Índice de Massa Corporal , Feminino , Humanos , Modelos Biológicos , Modelos Teóricos , Obesidade , Trabalho de Parto Prematuro/prevenção & controle , Gravidez , Proteínas Recombinantes/uso terapêutico , Contração Uterina/fisiologia
5.
Semin Cell Dev Biol ; 18(3): 340-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17582797

RESUMO

The regulation of uterine relaxation is poorly understood but research in myometrial tissue and other types of smooth muscle has defined a number of receptors, ion channels and regulatory proteins that are likely to be involved. Some of these proteins are substrates for protein kinases, especially cyclic nucleotide dependent kinases. More research is necessary to identify the key molecules involved in the maintenance of uterine quiescence in pregnancy. The use of tocolytics in preterm labour remains controversial; there is a need to identify better pharmacological targets to provoke safe and selective uterine relaxation and improve neonatal outcome.


Assuntos
Miométrio/fisiologia , Tocolíticos/uso terapêutico , Contração Uterina , Útero/efeitos dos fármacos , Útero/metabolismo , Animais , Feminino , Humanos , Relaxamento Muscular , Trabalho de Parto Prematuro/tratamento farmacológico , Trabalho de Parto Prematuro/metabolismo , Gravidez , Proteínas Quinases/metabolismo , Tocolíticos/metabolismo , Contração Uterina/efeitos dos fármacos
6.
J Pharmacol Exp Ther ; 321(3): 1118-26, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17351104

RESUMO

Ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl)amino] phenoxy]propyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640) was characterized as a new potent and selective beta(3)-adrenoceptor agonist for the treatment of preterm labor. SAR150640 and its major metabolite, the corresponding acid 4-[trans-4-[((2S)-2-hydroxy-3-[4-hydroxy-3[(methylsulfonyl) amino] phenoxy]propyl)amino]cyclohexyl]benzoic acid (SSR500400), showed high affinity for beta(3)-adrenoceptors (K(i) = 73 and 358 nM) and greater potency than (-)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native beta(3)-adrenoceptors (pEC(50) = 6.5, 6.2, and 5.1, respectively). SAR150640 and SSR500400 also increased cAMP production in membrane preparations from human uterine smooth muscle cells (UtSMC), which also express native beta(3)-adrenoceptors (pEC(50) = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no beta(1)- or beta(2)-agonist or antagonist activity in guinea pig atrium and trachea, or in human isolated atrium and bronchus preparations. Both compounds concentration-dependently inhibited spontaneous contractions in human near-term myometrial strips, with greater potency than salbutamol and 4-[3-[(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) (pIC(50) = 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V(1)a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F(2alpha). In vivo, after intravenous administration, SAR150640 (1 and 6 mg/kg), but not atosiban (6 mg/kg), dose-dependently inhibited myometrial contractions in conscious unrestrained female cynomolgus monkeys, with no significant effects on heart rate or blood pressure. In contrast, salbutamol (50 and 250 microg/kg) had no inhibitory effect on uterine contractions, but it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Benzoatos/farmacologia , Trabalho de Parto Prematuro/prevenção & controle , Sulfonamidas/farmacologia , Tocolíticos/farmacologia , Agonistas Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Animais , Benzoatos/química , Benzoatos/metabolismo , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , AMP Cíclico/metabolismo , Feminino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Isoproterenol/farmacologia , Macaca fascicularis , Estrutura Molecular , Miométrio/citologia , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Ocitocina/farmacologia , Gravidez , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 3/genética , Sulfonamidas/química , Sulfonamidas/metabolismo , Tocolíticos/química , Tocolíticos/metabolismo , Transfecção , Contração Uterina/efeitos dos fármacos , Vasotocina/análogos & derivados , Vasotocina/farmacologia
7.
J Reprod Med ; 50(11): 817-20, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16419627

RESUMO

OBJECTIVE: To compare the effect of prolonged maternal intravenous MgSO4 administration on amniotic fluid and serum concentrations of magnesium over time in preterm labor patients. STUDY DESIGN: Patients at 24-34 weeks of singleton gestation who presented with contractions (> 8 in 60 minutes) underwent amniocentesis to rule out intrauterine infection after signing an informed consent form. Some of these women who were clinically judged to have preterm labor received intravenous MgSO4: a 4-g loading dose followed by a 2 g/h maintenance dose. For technical reasons some patients had amniocentesis performed before initiation of MgSO4 (controls), while others had the procedure during tocolytic therapy (study subjects). Duration of treatment until amniocentesis was recorded, and blood samples were drawn at the time of amniocentesis. Maternal serum and amniotic fluid magnesium levels were measured using a colorimetric end point method. Data were evaluated using the Student t test and linear regression analysis. RESULTS: Mean magnesium levels in maternal serum rose from 1.74 +/- 0.2 mg/dL in controls to 4.01 +/- 0.4 mg/dL in the study group. Mean magnesium levels in Mean magnesium levels in amniotic fluid were 1.41 +/- 0.18 mg/dL in the controls versus 2.28 +/- 0.53 mg/dL in the treatment group. Duration of MgSO4 treatment ranged from 3 to 22 hours. Amniotic fluid magnesium concentrations increased significantly during therapy (correlation coefficient = 0.89; p < 0.001), while maternal serum levels remained stable over time (correlation coefficient between maternal serum levels and time = -0.39; p=0.34). CONCLUSION: Although maternal serum magnesium levels remained stable with intravenous MgSO4 therapy, concentrations continued to rise in amniotic fluid over time. However, amniotic fluid magnesium levels never exceeded maternal serum concentrations during the study period.


Assuntos
Líquido Amniótico/química , Sulfato de Magnésio/administração & dosagem , Magnésio/análise , Trabalho de Parto Prematuro/terapia , Tocolíticos/administração & dosagem , Adulto , Amniocentese , Líquido Amniótico/metabolismo , Colorimetria , Feminino , Humanos , Infusões Intravenosas , Modelos Lineares , Magnésio/sangue , Magnésio/metabolismo , Sulfato de Magnésio/metabolismo , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Tocólise/métodos , Tocolíticos/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-14683691

RESUMO

Preterm delivery (<37 weeks of gestation) is the major obstetrical complication in developed countries, yet attempts to delay labour and prolong pregnancy have largely been unsuccessful. One of the many reasons it is so difficult to prevent preterm birth is that the nature of preterm labour changes as a function of gestational age, maternal lifestyle factors or infection, to list a few of the reasons. The inhibitors of prostaglandin endoperoxide H synthase (PGHS), known as the Non-steroidal Antiinflammatory Drugs, have been viewed with interest as tocolytics with promising effectiveness under most conditions of preterm labour. Three isoforms of PGHS exist; the first two, PGHS-1 and -2, have been studied for their catalytic activity, X-ray crystallographic structure, and physiological roles in the adult and the foetus. Mixed inhibitors and isoform-specific inhibitors of PGHS have been developed, and their roles in delaying preterm labour are examined and compared to other tocolytics.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Trabalho de Parto Prematuro/prevenção & controle , Tocólise , Tocolíticos/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Inibidores de Ciclo-Oxigenase/metabolismo , Feminino , Glucocorticoides/uso terapêutico , Humanos , Doadores de Óxido Nítrico/farmacologia , Ocitocina/antagonistas & inibidores , Gravidez , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Tocolíticos/metabolismo
9.
Ginekol Pol ; 73(8): 666-71, 2002 Aug.
Artigo em Polonês | MEDLINE | ID: mdl-12369292

RESUMO

OBJECTIVE: The aim of this study was the analysis of the effectiveness and safety of glyceryl trinitrate as a nitric oxide donor for treatment of preterm labour. PATIENTS AND METHODS: The study was carried out on 50 patients in preterm labour between 28 and 34 weeks of gestation receiving transdermal glyceryl trinitrate (GTN) patches (drug Nitroderm TTS 5 produced by Novartis Pharma AG, Bazylea). RESULTS: GTN patches appear to be a non-invasive method of suppressing uterine contractions in preterm labour. MAP and systolic blood pressure decreased significantly during the use of nitroglycerin. Diastolic blood pressure and maternal heart rate did not change during the treatment. Neither were significant changes in fetal heart rate or in fetal cardiotocographic recordings detected during or after the treatment. CONCLUSION: Transdermal glyceryl trinitrate (5 mg/day) may be promising as a safe and effective drug for treatment of preterm labour, especially in patients with higher blood pressure.


Assuntos
Doadores de Óxido Nítrico/uso terapêutico , Nitroglicerina/uso terapêutico , Trabalho de Parto Prematuro/tratamento farmacológico , Trabalho de Parto Prematuro/prevenção & controle , Tocolíticos/uso terapêutico , Administração Cutânea , Adulto , Feminino , Humanos , Hipertensão/tratamento farmacológico , Doadores de Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/metabolismo , Nitroglicerina/farmacologia , Gravidez , Terceiro Trimestre da Gravidez , Tocolíticos/metabolismo , Tocolíticos/farmacologia , Resultado do Tratamento , Contração Uterina/efeitos dos fármacos
10.
Am J Obstet Gynecol ; 186(5): 997-1004, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12015527

RESUMO

OBJECTIVE: The aims of this study were (1) to evaluate the usefulness of the new beta2-adrenergic stimulant KUR-1246 as a tocolytic agent and (2) to clarify the mechanisms that underlie the diverse inhibitory effects of beta2-stimulants that are seen in human myometria in vitro. STUDY DESIGN: The displacement of tritiated ([3H]) (-)CGP 12177 (0.4 nmol/L) by KUR-1246 and other beta2-stimulants was examined with human beta(1)- and beta2-receptors present on membrane fractions. The inhibitory effects of these beta2-stimulants on the term-pregnant human myometrium were compared with the use of isometric tension recording and microelectrode methods. Finally, the relationship between [3H]dihydroaloprenolol binding and the magnitude of the tocolytic effect of isoproterenol was examined. RESULTS: KUR-1246 was approximately 80 times and 7 times more selective for beta2-receptors than isoproterenol and ritodrine, respectively. The inhibitory effect of KUR-1246 was as strong as the inhibitory effect of the conventional beta2-adrenergic stimulants. A wide range of inhibitory effects was observed, even when high concentrations of isoproterenol or KUR-1246 were applied. There was a correlation between the degree to which isoproterenol suppressed contractions and the number of [3H]dihydroaloprenolol binding sites on the membrane in each muscle strip. CONCLUSION: KUR-1246 should be a very useful beta2-adrenergic stimulant for use as a tocolytic agent because of its high selectivity for the beta2-receptor and its potent inhibitory effect. The diversity of the inhibitory effects that are induced by beta2-stimulants is at least partly due to differences in beta2-receptor density among term-pregnant human myometria.


Assuntos
Acetamidas/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Parto Obstétrico , Miométrio/efeitos dos fármacos , Naftalenos/farmacologia , Gravidez/fisiologia , Receptores Adrenérgicos beta/metabolismo , Tocolíticos/farmacologia , Contração Uterina/efeitos dos fármacos , Acetamidas/metabolismo , Agonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/metabolismo , Adulto , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva , Di-Hidroalprenolol/metabolismo , Feminino , Humanos , Técnicas In Vitro , Isoproterenol/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Miométrio/fisiologia , Naftalenos/metabolismo , Concentração Osmolar , Tocolíticos/metabolismo
11.
Int J Gynaecol Obstet ; 73(3): 201-6, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11376665

RESUMO

OBJECTIVE: The aim of our study was the assessment of effectiveness of nitroglycerin as a donor of nitric oxide, administered in the form of transdermal therapeutic system, applied in the treatment of threatening preterm labor. PATIENTS AND METHODS: The study was carried out on 30 pregnant patients with the symptoms of threatening preterm labor between 27th and 34th week of gestation. The patients were given nitroglycerin in the form of transdermal system releasing 5 mg of nitroglycerin in 24 h. RESULTS: In our study the decrease in contractility and relaxation of uterus was observed in all obstetric patients. No changes in the fetal pulse rate and cardiotocographic tracing in the course of treatment and after completing treatment were observed. CONCLUSION: Nitroglycerin in the form of transdermal therapeutic system releasing nitric oxide may be an effective and safe tocolytic drug, however, further investigation needs to be performed.


Assuntos
Doadores de Óxido Nítrico/uso terapêutico , Nitroglicerina/uso terapêutico , Trabalho de Parto Prematuro/tratamento farmacológico , Tocolíticos/uso terapêutico , Administração Cutânea , Cardiotocografia , Monitoramento de Medicamentos , Feminino , Idade Gestacional , Humanos , Doadores de Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/metabolismo , Nitroglicerina/farmacologia , Trabalho de Parto Prematuro/diagnóstico , Trabalho de Parto Prematuro/metabolismo , Trabalho de Parto Prematuro/fisiopatologia , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Tocolíticos/metabolismo , Tocolíticos/farmacologia , Resultado do Tratamento , Ultrassonografia Pré-Natal , Contração Uterina/efeitos dos fármacos
12.
Biopharm Drug Dispos ; 20(1): 11-8, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10086833

RESUMO

A new antirheumatic, TAK-603, shows nonlinear pharmacokinetics in both animals and humans. To elucidate the mechanism of these nonlinear pharmacokinetics, in vivo and in vitro metabolism of 14C-labeled TAK-603 ([14C]TAK-603) was studied using rats as these resemble humans in their metabolic profiles. After intravenous injection of [14C]TAK-603 to rats at doses of 1, 5, and 15 mg kg(-1), the total body clearance of unchanged drug decreased significantly with increasing dose, whereas the apparent distribution volume did not alter remarkably. Thus, saturation in the elimination processes was considered to be a factor responsible for the nonlinear pharmacokinetics. The disappearance of unchanged drug from the circulation, however, followed a dose-dependent first-order process, indicating that the nonlinearity observed was not merely due to saturation of the elimination capacity. In vitro studies using rat liver microsomes showed that TAK-603 competitively inhibited CYP-catalysed nifedipine oxidation and also that the demethylated metabolite M-I, the major metabolite in rats and humans, competitively inhibited the oxidation of nifedipine. These results suggested that inhibition by M-I of the metabolism of the parent drug (i.e. product-inhibition) may be the most likely factor responsible for the nonlinear pharmacokinetics of TAK-603.


Assuntos
Antirreumáticos/farmacocinética , Dinâmica não Linear , Quinolinas/farmacocinética , Triazóis/farmacocinética , Administração Oral , Animais , Antirreumáticos/sangue , Antirreumáticos/metabolismo , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Interações Medicamentosas , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Nifedipino/metabolismo , Oxirredução , Quinolinas/sangue , Quinolinas/metabolismo , Ratos , Ratos Wistar , Distribuição Tecidual , Tocolíticos/metabolismo , Triazóis/sangue , Triazóis/metabolismo
13.
Xenobiotica ; 27(11): 1147-54, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9413918

RESUMO

1. The objective of this study was to determine (1) the molecular site(s) of sulphoconjugation of fenoterol; (2) the human phenolsulphotransferase (PST) isoform(s) involved; and (3) the stereochemistry of the enzymatic reaction. 2. Using the human Hep G2 cell line, hplc isolation and FAB/ms/ms, it was determined that fenoterol is sulphated both in the 4'-hydroxyphenyl position and in one of the 3',5'-dihydroxyphenyl positions. 3. Recombinant human M-PST preferentially sulphated the 4'-hydroxyphenyl position. In contrast, recombinant P-PST exclusively sulphated the 3',5'-hydroxyphenyl position. 4. The M-PST-catalysed sulphation of the 4'-hydroxyphenyl position was highly selective for the active RR-enantiomer, whereas the sulphation of the 3',5'-dihydroxyphenyl position was slightly selective for the opposite SS-enantiomer. 5. The P-PST-catalysed sulphation of the 3',5'-hydroxyphenyl position was selective for the inactive SS-enantiomer.


Assuntos
Broncodilatadores/metabolismo , Fenoterol/metabolismo , Sulfatos/metabolismo , Sulfotransferases/metabolismo , Tocolíticos/metabolismo , Carcinoma Hepatocelular , Cromatografia Líquida de Alta Pressão , Humanos , Isoenzimas/metabolismo , Neoplasias Hepáticas , Proteínas Recombinantes/metabolismo , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Estereoisomerismo , Especificidade por Substrato , Radioisótopos de Enxofre , Células Tumorais Cultivadas
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