Nimodipine: Drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia

Blardi, Patrizia

doi:10.1067/mcp.2002.128127

Cited by 39 publications

(29 citation statements)

References 20 publications

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“…Our results demonstrated, however, that the mean half-life of nimodipine for the two formulations tested was 27.83 h (test formulation) and 32.78 h (reference formulation). Such a discrepancy could be due to the greater sensitivity of our method, with a limit of quantification of 100 pg/mL, while values found in previous studies were in the range 0.24 to 5 ng/mL (Krol et al, 1984;Jackobsen et al, 1986;Rosseel et al, 1990;Qian, Gallo, 1992;Fischer et al, 1993;Yan et al, 1993;Mück, 1995;Aymard et al, 1998;Gualano et al, 1999;López et al, 2000;Blardi et al, 2002;Qiu et al, 2004;Zhonggui et al, 2004;Nirogi et al, 2006). This improved sensitivity enabled the determination of plasma drug concentrations up to 48 h after drug administration, which was not possible in other studies that allowed the measurement of plasma drug levels only up to 10 h after drug administration.…”

Section: Pharmacokinetic Studymentioning

confidence: 61%

“…(Yan, Ding, Liu, 1993;Lian-Quing, Heng-Shan, Gang, 1993;Dollery, 1999;Blardi et al, 2002;Qiu et al, 2004;Zhonggui et al, 2004;Hernandez-Hernandez et al, 2002). Previous studies showed these data, but sampling was concluded between 5 and 10h after dosing, thereby possibly missing a longer elimination phase.…”

Section: Pharmacokinetic Studymentioning

confidence: 76%

“…The present LC-MS-MS method offered an LLOQ of 100 pg/mL with a mean accuracy of 7.0% and a mean precision of 103.0% (n=5), which is more sensitive than or comparable to reported methods (Krol et al, 1984;Jackobsen et al, 1986;Rosseel Bogaert, Huyghens, 1990;Qian, Gallo, 1992;Aymard et al, 1998;López et al, 2000;Blardi et al, 2002;Mück, 1995;Qiu et al, 2004;Nirogi et al, 2006;Qin et al, 2008). Data for LLOQ are presented in Table II.…”

Section: Linearity and Lower Limit Of Quantificationmentioning

confidence: 97%

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Determination of nimodipine in plasma by HPLC-MS/MS and pharmacokinetic application

Nascimento

Moraes

Bezerra

et al. 2010

Braz. J. Pharm. Sci.

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To develop and validate a rapid, specific and highly sensitive method to quantify nimodipine in human plasma using dibucaine as the internal standard (IS). The analyte and IS were extracted from plasma samples by liquid-liquid extraction using hexane-ethyl acetate (1:1 v/v). The chromatographic separation was performed on a Varian ® Polaris C18 analytical column (3 mm, 50 x 2.0 mm) and pre-column Securityguard TM C18 (4.0 x 3.0 mm) with a mobile phase of Acetonitrile-Ammonium acetate 0.02 ml/L (80:20v/v). The method had a chromatographic run time of 4.5 min and linear calibration curve over the range of 0.1-40 ng/mL (r > 0.9938). The limit of quantification was 100 pg/mL. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. This validated method was successfully applied in determining the pharmacokinetic profile of nimodipine tablets of 30 mg administered to 24 healthy volunteers. The proposed method of analysis provided a sensitive and specific assay for nimodipine determination in human plasma. The time for the determination of one plasma sample was 4.5 min. This method is suitable for the analysis of nimodipine in human plasma samples collected for pharmacokinetic, bioavailability or bioequivalence studies in humans.Uniterms: Nimodipine/determination in plasma. Nimodipine/pharmacokinetic profile. Nimodipine/ quantitative analysis. Pharmacokinetics/method validation.Um método rápido, específico e sensível para quantificar nimodipino em plasma humano usando dibucaína como padrão interno (IS) é descrito. O analito e o IS foram extraídos das amostras de plasma por extração líquido-líquido usando hexano-acetato de etila (1:1 v/v). A separação cromatográfica foi realizada utilizando-se uma coluna analítica C18 Varian ® Polaris (3 mm, 50 x 2,0 mm) e uma pré-coluna Securityguard TM C18 (4,0 x 3,0 mm) e acetonitrila-acetato de amônia 0,02 mol/L (80:20 v/v) como fase móvel. O método apresentou tempo total de corrida de 4,5 min e curva de calibração linear com concentrações entre 0,1-40 ng/mL (r > 0,9938). O limite de quantificação foi de 100 pg/mL. Os valores de precisão e exatidão foram obtidos por meio da análise das amostras de controle de qualidade. A análise de uma única amostra de plasma foi realizada em 4,5 minutos. A metodologia validada foi aplicada na determinação do perfil farmacocinético do nimodipino, comprimido de 30 mg administrado em 24 voluntários saudáveis. O método para quantificar nimodipino em plasma é adequado para aplicação em estudos farmacocinéticos, biodisponibilidade e bioequivalência em humanos.

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Section: Pharmacokinetic Studymentioning

confidence: 61%

Section: Pharmacokinetic Studymentioning

confidence: 76%

Section: Linearity and Lower Limit Of Quantificationmentioning

confidence: 97%

See 1 more Smart Citation

Determination of nimodipine in plasma by HPLC-MS/MS and pharmacokinetic application

Nascimento

Moraes

Bezerra

et al. 2010

Braz. J. Pharm. Sci.

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“…24,25 This effect on cerebral blood flow is reduced or absent in patients treated with other dihydropyridine CCBs. 26 -28 In patients with cerebral ischemia, the doses of nimodipine used produce plasma levels over 200 nmol/L in plasma, 29 above the IC50 value for MR. In contrast, commonly achieved plasma levels of the other MR-active dihydropyridine CCBs such as felodipine (peak plasma concentration Ϸ25 nmol/L at 10 mg 30 ) and nitrendipine (peak plasma concentration Ϸ50 nmol/L at 20 mg 31 ) are much lower than their respective IC50 values for MR.…”

Section: Discussionmentioning

confidence: 99%

A Number of Marketed Dihydropyridine Calcium Channel Blockers Have Mineralocorticoid Receptor Antagonist Activity

et al. 2008

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Abstract-Calcium channel blockers are widely used antihypertensives. Mineralocorticoid receptor antagonists are also used to treat hypertension and heart failure. We report here that a number of widely used dihydropyridine class calcium channel blockers are able to inhibit aldosterone-induced activation of mineralocorticoid receptor. These dihydropyridines varied in the extent of their effect on mineralocorticoid receptor, with nimodipine and felodipine the most potent and amlodipine the least. In contrast, both diltiazem and verapamil, nondihydropyridine calcium channel blockers, had no effect on mineralocorticoid receptor. These dihydropyridines compete with aldosterone for binding and block aldosterone-induced coactivator recruitment to mineralocorticoid receptor. The mineralocorticoid receptor S810L mutant, which is activated by steroidal mineralocorticoid receptor antagonist such as eplerenone, is inhibited by these drugs. Furthermore, nimodipine decreased aldosterone-induced expression of the mineralocorticoid receptor target gene epithelial sodium channel gamma subunit in adrenalectomized rats, demonstrating that dihydropyridine calcium channel blockers can function as mineralocorticoid receptor antagonists in vivo. Molecular modeling indicates that dihydropyridines dock into the ligand binding domain of mineralocorticoid receptor in a consensus pose that partially overlaps with steroidal mineralocorticoid receptor antagonists. Together, our data suggest that, in addition to their calcium channel blocking activity, a number of dihydropyridine calcium channel blockers also have mineralocorticoid receptor antagonist activity at high doses, a finding which may thus prove useful for the design of novel antihypertensive drugs in the future. Key Words: calcium channel blockers Ⅲ aldosterone Ⅲ mineralocorticoid receptor antagonist Ⅲ dihydropyridine H ypertension is a widespread public health problem and a major risk factor for cardiovascular and renal disease. Numerous antihypertensive drugs have been developed to lower blood pressure (BP); these drugs target a number of mechanisms and are often used in combination. 1,2 Calcium channel blockers (CCBs) are among the most frequently used antihypertensives and are grouped into 2 classes based on the chemical structures: the dihydropyridines such as amlodipine and nifedipine, and nondihydropyridines (diltiazem and verapamil). 3 Another heavily targeted mechanism for treatment of hypertension is the renin-angiotensin-aldosterone system. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are among the standard therapies for BP control. 4 Mineralocorticoid receptor (MR) antagonists, such as eplerenone, block MR activation and show similar BP lowering efficacy as ACEi or ARB. 5,6 Targeting multiple mechanisms provides an advantage in control of hypertension, as most hypertensive patients require 2 or more medications to achieve their BP goal. 7Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist acti...

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“…Recently, NM has been shown to be effective in ameliorating memory degeneration and preventing senile dementia in the old age (3,4). However, the clinical efficacy of NM is strongly limited by its poor water solubility (2.30 μg/ml) and low oral bioavailability (∼13%) (5,6). Apart from the poor water solubility, extensive first-pass metabolism by Cytochrome P450-3A4 (CYP3A4) isoenzymes and P-glycoprotein (P-gp) mediated efflux are also responsible for the low oral bioavailability of the NM (7).…”

Section: Introductionmentioning

confidence: 99%

Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS) of Nimodipine

Kale

Patravale

2008

AAPS PharmSciTech

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Abstract. The ability of self-emulsifying drug delivery systems (SEDDS) to improve solubility, dissolution rate and bioavailability of a poorly water-soluble calcium channel blocker, nimodipine (NM) was evaluated in the present investigation. Solubility of NM in various oils, surfactants and cosurfactants was determined. The influence of the ratio of oil to surfactant + cosurfactant, pH of aqueous phase on mean globule size of resulting emulsions was studied by means of photon correlation spectroscopy. The NM loaded SEDDS selected for the in vitro and in vivo studies exhibited globule size less than 180 nm. In vitro dissolution studies indicated that NM loaded SEDDS could release complete amount of NM irrespective of the pH of the dissolution media. Pharmacokinetics of NM suspension, NM oily solution, NM micellar solution and NM SEDDS were evaluated and compared in rabbits. Relative bioavailability of NM in SEDDS was significantly higher than all the other formulations. NM loaded SEDDS were subjected to various conditions of storage as per ICH guidelines for 3 months. NM SEDDS successfully withstood the stability testing.KEY WORDS: in vitro drug release; low oral bioavailability; nimodipine; pharmacokinetics; selfemulsifying drug delivery systems (SEDDS).

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Nimodipine: Drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia

Abstract: Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.

Cited by 39 publications

References 20 publications

Determination of nimodipine in plasma by HPLC-MS/MS and pharmacokinetic application

Determination of nimodipine in plasma by HPLC-MS/MS and pharmacokinetic application

A Number of Marketed Dihydropyridine Calcium Channel Blockers Have Mineralocorticoid Receptor Antagonist Activity

Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS) of Nimodipine

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