Mechanistic Framework to Predict Maternal-Placental-Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach.

Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.

ABCG2 c.421C>A polymorphism alters nifedipine transport to breast milk in hypertensive breastfeeding women.

Nifedipine, a known substrate to breast cancer resistance protein (ABCG2/BCRP), is used for the treatment of hypertension during breastfeeding. This study aimed to evaluate the effect of ABCG2 c.421C>A on nifedipine transfer to breast milk (BM) in hypertensive women. Nineteen hypertensive breastfeeding women treated with 20 mg nifedipine every 12 hours were investigated. Blood and BM samples were collected simultaneously 15-30 days after delivery and at least 15 days after drug treatment. Patients genotyped as ABCG2 c.421CC showed nifedipine plasma and BM concentrations ranging from 8.32-178.1 ng/mL and 4.8-58.5 ng/mL, respectively. ABCG2 c.421C>A showed a trend towards significance (p = 0.0793) on nifedipine in BM, with concentrations approximately 3 times higher in the heterozygous 421 CA (29 ng/mL) in comparison to 421 CC (10.5 ng/mL). Nifedipine BM/plasma ratio was significantly lower in 421CC when compared to 421CA (p = 0.01). In conclusion, ABCG2 c.421C>A polymorphism is associated with higher transfer of nifedipine to BM.

Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women.

AIMS: Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. METHODS: The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 h). On the 34th week of gestation, serial blood samples were collected (0-12 h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. RESULTS: The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41 ng ml-1 , time to reach Cmax (tmax ) 1.79 h, area under the plasma concentration vs. time curve from 0-12 h (AUC0-12 ) 235.99 ng.h ml-1 , half-life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and ClT /F 84.77 l h-1 . The parameters for T2DM group were: Cmax 23.52 ng ml-1 , tmax 1.48 h, AUC0-12 202.23 ng.h ml-1 , t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (ClT /F) 98.94 l h-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. CONCLUSIONS: There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.

Analysis of nifedipine in human plasma and amniotic fluid by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics in hypertensive pregnant women.

Nifedipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension in pregnant women. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for analysis of nifedipine in human plasma and amniotic fluid. Separation of nifedipine and nitrendipine (IS) was performed using a LiChroCART(®) RP-Select B column and a mixture of water:acetonitrile:glacial acetic acid (30:70:0.5 v/v) as the mobile phase. Aliquots of 500µL of biological samples were extracted at pH 13 using dichloromethane:n-pentane (3:7 v/v). The validated method was applied to a study of the pharmacokinetics of nifedipine in human plasma and amniotic fluid samples collected up to 12h after administration of the last slow-release nifedipine (20mg/12h) dose to 12 hypertensive pregnant women. The estimated pharmacokinetic parameters of nifedipine showed a mean AUC(0-12) of 250.2ngh/mL, ClT/F of 89.2L/h, Vd/F of 600.0L and t1/2 5.1h. The mean amniotic fluid/plasma concentration ratio was 0.05. The methods proved to be highly sensitive by showing a lower quantification limit of 0.1ng/mL for both matrices. And this study reports for the first time the complete development and validation of the method to quantify nifedipine in amniotic fluid using LC-MS-MS.

Nifedipine in semi-solid formulations for topical use in peripheral vascular disease: preparation, characterization, and permeation assay.

Nifedipine (NFD) has been used for the treatment of cutaneous lesions caused by peripheral vascular disease and diabetic ulcers. NFD was formulated at 8% in three semi-solid formulations: Polaxamer 407 Lecithin Organogel (PLO), PLO plus Transcutol(®), and an oil-in-water (o/w) emulsion. In vitro release and permeation tests were carried out using a synthetic (cellulose acetate) or natural membrane (pig ear skin), respectively, mounted in a Franz-type diffusion cell at 37°C in a constant water bath. As a receptor solution, isotonic phosphate buffer at pH 7.4 was used. All samples were analyzed by high-performance liquid chromatography by employing a previously validated method. The drug flow values were 6.126 ± 0.288, 4.030 ± 0.081, and 6.660 ± 0.254 µg/cm(2)/h for PLO, PLO plus Transcutol(®), and o/w emulsion, respectively. The three formulations did not show significant differences in drug flow, considering p > 0.05. Furthermore, their penetration profiles in both the epidermis and dermis were statistically different. Thus, the incorporation of NFD in PLO, PLO plus Transcutol(®), and o/w emulsion changed the drug thermodynamic activity, as expected. In addition, Transcutol(®) increased the solubility of NFD in the formulation and promoted its penetration in both the epidermis and dermis.

Development and evaluation of nifedipine controlled release tablets prepared using mucoadhesive swellable polymer.

Nifedipine is embedded in Gelcarin GP-379 to develop a prolonged release matrix. The effect of polymers levels (15, 20, 30 and 50% w/w), diluent type (lactose Fast Flo, DiTab, and Avicel PH-101), and drug levels (13, 20 and 30% w/w) on in vitro release rate of the drug were investigated. The formulation containing 13% nifedipine, 20% Gelcarin GP-379, and lactose Fast Flo controlled the dissolution rate of nifedipine and released approximately 51% drug at 8 h of testing dissolution. The use of different types of diluents, different drug levels, and different rotational speeds during dissolution testing did affect the drug release rate from the swellable matrices. The dissolution data were analyzed according to Higuchi model, zero order, first order, and Peppas kinetic model. Drug release was found to follow the anomalous diffusion model for swellable matrix.

Curso de Atualização em emergências médicas: aula 2: Urgências e emregências hipertensivas / Medical emergencies actualization course: class 2: hypertensive urgencies and emergencies

A hipertensão arterial é uma condição clínica com alta prevalência em todo o mundo, sendo fundamental estar atento às suas possíveis complicações. As emergências hipertensivas são condições associadas a risco iminente de vida, associadas à perda rápida da função de órgãos-alvo. Nesses casos a redução da pressão arterial deve ser imediata, em horas ou minutos. Nas urgências hipertensivas esse risco também existe, mas a redução da pressão arterial pode ser mais gradual, em cerca de 24 horas.

The characterization of the activity of a bark extract from Fagara martinicensis on the rat vas deferens

OBJECTIVE: An aqueous extract made from the bark of Fagara martinicensis (family Rutaceae) was examined for its effect on the isolated rat vas deferens. METHOD: The investigation involved measurement of isometric tension in the prostatic and epididymal portions of the isolated rat vas deferens which was anchored in an organ bath with physiological solution. Non-cumulative doses of Fagara martinicensis (FM) were added to the bath and the effects examined in the presence of receptor antagonists to characterize the actions of FM. Results before and after antagonist additions were compared. RESULTS: Non-cumulative addition of FM (1.6 mg/ml to 14.1 mg/ml) produced contractions of both portions of the vas deferens, with the epididymal portion showing greater sensitivity to the effects of FM. The contractions consisted of a rhythmic component superimposed on a phasic and tonic component. All components of the contractions were abolished by prazosin (2.1 uM), a selective a1-adrenoreceptor antagonist, and therefore it was concluded that FM contractions are due to agonist activities on these receptors. Since stimulation of a1-adrenoreceptora results in the mobilization of extracellular calcium into the muscle, the involvement of extracellular calcium was investigated with calcium channel antagonist, nifedipine (0.11-6.0 uM). Nifedipine inhibited all components of the contraction. This effect indicates that entry of extracellular calcium into the muscle was involved in all components of the contraction and further confirms a1-adrenoreceptor agonist action of Fagara martinicensis. CONCLUSIONS: Fagara martinicensis may therefore be a potential source of drugs with a1-adrenoreceptor agonist properties. (AU)

The use of short-acting nifedipine in pediatric patients with hypertension.

OBJECTIVE: To evaluate the use of short-acting nifedipine for treatment of severe hypertension in children. STUDY DESIGN: A retrospective chart review of 520 nifedipine doses given for severe hypertension in 117 pediatric patients was completed. Nifedipine dose, systolic and diastolic blood pressures before and within 2 hours of the dose, and side effects were recorded. Pre- and post-dose mean arterial pressure (MAP) and percent reductions in MAP and systolic and diastolic blood pressure were calculated. Age, dose, primary diagnosis, and use of other antihypertensive agents were examined with respect to blood pressure reduction. RESULTS: Of the doses received, 35% were associated with > or =25% reduction in MAP, a degree of MAP reduction previously associated with hypertension treatment complications. MAP percent reduction was correlated with nifedipine dose adjusted for weight (r = 0.24, P<.001). Mean nifedipine doses per kilogram were larger in patients who had > or =25% MAP reduction compared with those who had <25% MAP reduction (0.26 +/- 0.12 mg/kg vs. 0.21 +/- 0.11 mg/kg, F = 29.01, P <.001). Adolescents received lower nifedipine doses per kilogram and had lower percent reduction in blood pressure compared with younger children. No clinically significant side effects were noted after administration of nifedipine. CONCLUSION: Precipitous reductions in blood pressure are ameliorated by decreasing the initial nifedipine dose to < or =0.25 mg/kg in pediatric patients. Short-acting nifedipine use in pediatric patients with hypertension in a hospital setting is safe.

Angina inestable: los calcibloqueantes sin betabloqueantes no previenen la recurrencia de la angina, los procedimientos intervencionistas, ni la insuficiencia cardíaca / Calcium channel bloquer agentes, not associated to betabloquers, do not prevent recurrent angina, further invasive procedures or pump failure in patients hospitalized for unstable angina

Antecentes. Los calciantagonistas (CA) deberían ser eficaces en reducir la mortalidad y el infarto (IAM) no fatal en la angina inestable (AI). Se ha demostrado que los CA proporcionan alivio sintomático y mejor evolución. Objetivo. Investigar si los CA en la AI disminuyen la muerte y el IAM no fatal, previenen la recurrencia de la angina y mejoran la evolución. Material y métodos. Análisis en la base de datos del estudio ENAI (Enalapril en la Angina Inestable) que sigue durante 7 días a 1022 pacientes con AI. Indicación de betabloqueantes (BB) y CA a criterio de los participantes. Resultados. La angina recurrente y los procedimientos invasivos no son diferentes en la AI previamente tratada con CA (RR 1,02; IC95 0,74 - 1,40; P 0,8958). En 1022 pacientes los eventos secundarios aumentan en los no tratados (53,3 por ciento en 629) en relación a los tratados con CA cuando se asocian a los BB (46,7 por ciento en 392; RR 1,39; IC95 1,19 - 1,62; P 0,00003) Para Diltiazem-BB los eventos secundarios disminuyen desde un 61,3 por ciento al 38,7 por ciento (RR 1,74; ; IC95 1,39 - 2,18; P 0,0000), similar con otros CA-BB. Reducen los eventos secundarios del 66 por ciento al 34 por ciento en el grupo con SD del ST/ST normal (RR del 1,92; IC95 1,05 - 3,51; P 0,0335). Conclusiones. La indicación de CA sin BB en AI no disminuye los eventos isquémicos secundarios ni el desarrollo de insuficiencia cardíaca. Indicados en AI con SD del ST. (AU)

Angina inestable: los calcibloqueantes sin betabloqueantes no previenen la recurrencia de la angina, los procedimientos intervencionistas, ni la insuficiencia cardíaca / Calcium channel bloquer agentes, not associated to betabloquers, do not prevent recurrent angina, further invasive procedures or pump failure in patients hospitalized for unstable angina

Antecentes. Los calciantagonistas (CA) deberían ser eficaces en reducir la mortalidad y el infarto (IAM) no fatal en la angina inestable (AI). Se ha demostrado que los CA proporcionan alivio sintomático y mejor evolución. Objetivo. Investigar si los CA en la AI disminuyen la muerte y el IAM no fatal, previenen la recurrencia de la angina y mejoran la evolución. Material y métodos. Análisis en la base de datos del estudio ENAI (Enalapril en la Angina Inestable) que sigue durante 7 días a 1022 pacientes con AI. Indicación de betabloqueantes (BB) y CA a criterio de los participantes. Resultados. La angina recurrente y los procedimientos invasivos no son diferentes en la AI previamente tratada con CA (RR 1,02; IC95 0,74 - 1,40; P 0,8958). En 1022 pacientes los eventos secundarios aumentan en los no tratados (53,3 por ciento en 629) en relación a los tratados con CA cuando se asocian a los BB (46,7 por ciento en 392; RR 1,39; IC95 1,19 - 1,62; P 0,00003) Para Diltiazem-BB los eventos secundarios disminuyen desde un 61,3 por ciento al 38,7 por ciento (RR 1,74; ; IC95 1,39 - 2,18; P 0,0000), similar con otros CA-BB. Reducen los eventos secundarios del 66 por ciento al 34 por ciento en el grupo con SD del ST/ST normal (RR del 1,92; IC95 1,05 - 3,51; P 0,0335). Conclusiones. La indicación de CA sin BB en AI no disminuye los eventos isquémicos secundarios ni el desarrollo de insuficiencia cardíaca. Indicados en AI con SD del ST.

Nifedipina: farmacocinética y adecuado uso terapéutico / Nifedipine: pharmacokinetics and adequeate therapeutic use

Se presenta una visión global de diversos aspectos de la farmacodinamia, farmacocinética, consideraciones especiales, indicaciones terapéuticas y efectos adversos de la nifedipina y su implicación en población mexicana. Se revisa la utilidad real de la nifedipina por vía sublingual en la urgencia ipertensiva, en el manejo de la hipetensión arterial y su uso en México. Asimismo, se valora el mito de su riesgo en los pacientes a quiene se les administra nifedipina y se explica la evidencia de que este riesgo solo se presenta con la formulación de liberación rápida. Con base en esta revisión, se describen algunas conclusiones útiles para el médico que prescribe nifedipina. Se recomienda evitar la nifedipina de acción corta (cápsula) por la ruta oral en el tratamiento de la hipertensión arterial. Igualmente debe evitarse el uso de las cápsulas con nifedipina por vía sublingual en el manejo de la urgencia hipertensiva, ya que esta presentación es inadecuada para la absorción sublingual. Por otro lado, el uso de la nifedipina de acción prolongada se puede considerar de primera elección en el manejo de la hipertensión arterial

[Clinical pharmacokinetics of calcium antagonists]. / Farmacocinética clínica de los antagonistas del calcio.

Calcium antagonists (C.A.T.S.) represent a heterogeneous group of pharmacons, being its mechanism of action the inhibition of the flow of entrance of calcium through type L depending-voltage channels of the membranes of the excitable cells. They are very liposoluble molecules which are well absorbed after oral prescription (90-100%); they show an important effect in their first step, they join the serum proteins in a high proportion, present a wide tissue distribution, they are quickly biotransformed in the liver and only a minimum proportion is discharged by urine without any modification. Most of the dihydropiridines are liposoluble showing pka values < 4, so that in a physiologic ph of 7.4, up to 95% of the molecule is found in a nonionized neuter form, passing easily the cell membranes through lipidic and hydrophilic routes and as a consequence their actions will appear and disappear rapidly. Amlodipine is a dihydropiridine with a pharmacologic profile different from other C.A.T.S. Due to its physical and chemical properties which confer basic and hydrosoluble features (pka = 8.6), with a physiologic ph, almost 95% of the pharmacon is found in an ionized condition, passing the biological membranes through the lipophylic routes, showing a high affinity for membrane phospholipids where they interact forming an ionic binding. The pharmacon accumulates at this level and from there it spreads very slowly towards its receptors in the calcium channel; this slow association speed explains why the vasodilator effects of amlodipine appear in a gradual manner reaching their maximum effect after 6-10 hours.

Farmacocinetica clinica de los antagonistas del calcio / Clinical pharmacokinetics of the calcium antagonists

Los antagonistas del calcio (A Ca) constituyen un grupo heterogéneo de fármacos, siendo su mecanismo de acción el de inhibir el flujo de entrada de Ca a través de los canales voltaje-dependientes tipo L de las membranas de las células excitables. Son moléculas muy liposolubles que tras su administración por vía oral se absorben muy bien (90-100 por ciento) sufren un importante efecto de primer paso hepático. Se unen en una alta proporción a las proteínas plasmáticas, presentan una amplia distribución tisular, se biotransforman rápidamente en el hígado y sólo una mínima parte se elimina sin modificr por orina. La mayoría de las dihidropiridinas son liposolubles, presentando valores de pka < 4, por lo que en ph fisiológico (pH 7,4), hasta el 95 por ciento de la molécula se encuentra en forma neutra, no-ionizada, atravesando fácilmente las membranas celulares a través de vías lipo e hidrofílicas y como consecuencia, sus acciones van a aparecer y desaparecer rápidamente. La amlodipina es una dihidropiridina, cuyo perfil farmacocinético difiere de otros A Ca. Debido a sua propiedades fisicoquímicas que le confieren un carácter básico (p Ka = 8.6) e hidrosoluble, a pH fisiológico casi el 95 por ciento del fármaco se encuentra en estado ionizado, atravessando las membranas biológicas a través de vías lipofílicas, teniendo una alta afinidad por los fosfolípidos de membrana, con los que interacciona formando un enlace iónico. El fármaco se acumula a este nível y desde ahí se difunde muy lentamente hacia su receptor en el canal de Ca. Esta lenta velocidad de asociación explica por qué los efectos vasodilatadores de la Amplodipina aparecen en forma gradual alcanzando su efecto máximo al cabo de 6-10 horas. (AU)

Farmacocinetica clinica de los antagonistas del calcio / Clinical pharmacokinetics of the calcium antagonists

Los antagonistas del calcio (A Ca) constituyen un grupo heterogéneo de fármacos, siendo su mecanismo de acción el de inhibir el flujo de entrada de Ca a través de los canales voltaje-dependientes tipo L de las membranas de las células excitables. Son moléculas muy liposolubles que tras su administración por vía oral se absorben muy bien (90-100 por ciento) sufren un importante efecto de primer paso hepático. Se unen en una alta proporción a las proteínas plasmáticas, presentan una amplia distribución tisular, se biotransforman rápidamente en el hígado y sólo una mínima parte se elimina sin modificr por orina. La mayoría de las dihidropiridinas son liposolubles, presentando valores de pka < 4, por lo que en ph fisiológico (pH 7,4), hasta el 95 por ciento de la molécula se encuentra en forma neutra, no-ionizada, atravesando fácilmente las membranas celulares a través de vías lipo e hidrofílicas y como consecuencia, sus acciones van a aparecer y desaparecer rápidamente. La amlodipina es una dihidropiridina, cuyo perfil farmacocinético difiere de otros A Ca. Debido a sua propiedades fisicoquímicas que le confieren un carácter básico (p Ka = 8.6) e hidrosoluble, a pH fisiológico casi el 95 por ciento del fármaco se encuentra en estado ionizado, atravessando las membranas biológicas a través de vías lipofílicas, teniendo una alta afinidad por los fosfolípidos de membrana, con los que interacciona formando un enlace iónico. El fármaco se acumula a este nível y desde ahí se difunde muy lentamente hacia su receptor en el canal de Ca. Esta lenta velocidad de asociación explica por qué los efectos vasodilatadores de la Amplodipina aparecen en forma gradual alcanzando su efecto máximo al cabo de 6-10 horas.

Influence of renal failure on cytochrome P450 activity in hypertensive patients using a "cocktail" of antipyrine and nifedipine.

OBJECTIVE: Two substrates were coadministered in a "cocktail" approach to evaluate the contribution of renal failure to drug oxidation. PATIENTS: Nineteen hypertensive patients, nine of them with chronic renal failure (CLCR 38.9 vs 102.3 ml.min-1 1.73 m-2), were investigated after peroral administration of a combination of antipyrine (500 mg, in capsules) and nifedipine (10 mg, in Oxcord capsules) in the morning after an overnight fast. RESULTS: This "cocktail" approach made it possible to characterize in vivo the activities of different forms of cytochrome P450 in a single-study protocol using the total clearance of nifedipine and clearance for production of 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine (OHA) and norantipyrine (NORA). With this "cocktail" approach (antipyrine plus nifedipine), we can suggest a selective effect on the activities of cytochrome P450 forms associated with the formation of dehydronifedipine (P450 III A4) and of NORA in patients with mild renal failure under long-term antihypertensive therapy.

Interacción del jugo de grapefruit con la felopina y la nifedipina / Interaction of grapefruit juice with felopina and nifedipine

El jugo de grapefruit presenta interacción con los antagonistas del calcio derivados de a dihidroiridina como la felodipina, la nifedipina y la nitrendipina. La interacción, ue es mediada por una isoforma del citocroma P 450, produce un aumento en la biodisponibilidad de los inhibidores del calcio, que en algunos casos puede tener importancia clínica.