Felodipine

Felodipine is a selective L-type Ca²⁺ channel blocker with IC50 of 0.15 nM.

Ultrasound assisted dispersive liquid-liquid microextraction coupled with high performance liquid chromatography designated for bioavailability studies of felodipine combinations in rat plasma.[Pubmed:28189955]

J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Mar 1;1046:200-210.

Felodipine (FLD), a calcium channel antagonist, is commonly prescribed for the treatment of hypertension either with Metoprolol (MET) or Ramipril (RAM) in two different drug combinations. FLD has high plasma protein binding ability affecting its extraction recoveries from plasma samples. Hence, a specific ultrasound assisted dispersive liquid-liquid microextraction (UA-DLLME) method coupled with HPLC using photodiode array detector was developed and validated for the simultaneous determination of FLD, MET and RAM in rat plasma after oral administration of these combinations. The factors affecting UA-DLLME were carefully optimized. In this study, UA-DLLME method could provide simple and efficient plasma extraction procedures with superior recovery results. Under optimum condition, all target drugs were separated within 13min. The validation procedures was carried out in agreement with US-FDA guidelines and shown to be suitable for anticipated purposes. Linear calibration ranges were obtained in the range 0.05-2.0mugmL(-1) for FLD and MET and 0.1-2.0mugmL(-1) for RAM with detection limits of 0.013-0.031mugmL(-1) for all the studied drug combinations. The%RSD for inter-day and intra-day precisions was in range of 0.63-3.85% and the accuracy results were in the range of 92.13-100.5%. The validated UA-DLLME-HPLC method was successfully applied for the bioavailability studies of FLD, MET and RAM. The pharmacokinetic parameters were calculated for all the investigated drugs in rats after single-dose administrations of two different drug combinations. Although FLD was bioequivalent in the two formulations, a small increase in plasma levels of MET and RAM was found in the presence of FLD.

Formulation, evaluation and optimization of the felodipine nanosuspension to be used for direct compression to tablet for in vitro dissolution enhancement.[Pubmed:28375107]

Pak J Pharm Sci. 2016 Nov;29(6):1927-1936.

The oral bioavailability of Felodipine very low, nearly just 15% due to its limited solubility and high first pass metabolism. The present study was aimed to improve the rate of the dissolution of Felodipine by formulating a nano suspension of it by combination of high-speed homogenization and media milling technique. Stabilizers screened in this study were Poloxamer 401, HPMC K15M and Tween 80. Concentration of stabilizers were optimized by simplex lattice design for Mean Particle Size (MPS), Poly dispersity Index (PDI), saturation solubility (SS) and in vitro drug release in 30 min. The particle size of 201 nm and increase in saturation solubility of nearly 9 folds were obtained for optimize batch. The prepared nano suspension of drug was used as a granulating agent to form tablets having Microcrystalline Cellulose (MCC) as diluents. In vitro Drug release study indicates that more than 90% of the drug releases in 30 minutes. Preparing the nano suspension of the low solubility drug is an effective method to increase its saturation solubility. This nano suspension can be prepared effectively by combination of high-speed homogenization and media milling which is also very economical as well.

Multicomponent solid forms of felodipine: preparation, characterisation, physicochemical and in-vivo studies.[Pubmed:28134976]

J Pharm Pharmacol. 2017 Mar;69(3):254-264.

OBJECTIVES: This study aimed to improve biopharmaceutical parameters of the poorly soluble antihypertensive drug, Felodipine, by preparing multicomponent solid forms using three coformers, viz. imidazole, nicotinamide and malonic acid. METHODS: The multicomponent solid forms were prepared by mechanochemical synthesis and characterised by various analytical techniques. These solid forms were further assessed for their physicochemical parameters. Pharmacokinetic and in-vivo antihypertensive activity was performed in rats. KEY FINDINGS: Felodipine (FEL) was found to be cocrystallised with imidazole (FEL-IM) while it formed eutectic with nicotinamide (FEL-NCT) and malonic acid (FEL-MA). Cocrystal was sustained by NH...N and NH....O hydrogen-bonded network. Solubility and intrinsic dissolution studies in 0.1 N HCl (pH 1.2) revealed that eutectics exhibited higher solubility and release rate than cocrystal vis-a-vis pure drug and were found to be stable under accelerated storage condition. Significant enhancement of bioavailability was observed in eutectics (3.5- to twofold) and cocrystal (1.3-fold) compared with the pure drug. Antihypertensive activity of new solid forms in an animal model showed a marked decrease in systolic blood pressure. CONCLUSIONS: Mechanochemical approach was successful to prepare multicomponent solid forms that have the potential to improve biopharmaceutical parameters of the poorly soluble drug, FEL.

The influence of CYP3A5*3 and BCRPC421A genetic polymorphisms on the pharmacokinetics of felodipine in healthy Chinese volunteers.[Pubmed:28244604]

J Clin Pharm Ther. 2017 Jun;42(3):345-349.

WHAT IS KNOWN AND OBJECTIVE: The role of CYP3A5 in drug metabolism has been receiving attention because CYP3A5 may be more involved in the metabolism of CYP3A substrates in vivo than previously thought. The polymorphism of transporters, such as P-gp (P-glycoprotein) and breast cancer-related protein (BCRP), influences the metabolism of these substrates, and Felodipine is a substrate of P-gp. The aim of this study was to evaluate the pharmacogenetic variability in the disposition of Felodipine in healthy Chinese subjects. METHODS: A single dose of 5 mg Felodipine was orally administered to 45 healthy Chinese subjects. The serum concentration of Felodipine was measured by using LC/MS/MS. We detected the SNPs of cytochromes P450 enzymes and transporters, which play vital roles in drug metabolism and have a high frequency of mutation in Chinese population. RESULTS AND DISCUSSION: The area under the plasma concentration-time curve (AUC) within the time points 0 to 72 h (AUC(0-72) ) after Felodipine administration was significantly higher in subjects possessing the BCRP421AA alleles than in those with the BCRP421 CC or CA genotype (P = 0.034). The subjects with CYP3A5*3/*3 (n = 27) had higher Felodipine exposure than CYP3A5*1/*3 (n = 15) (P = 0.035). WHAT IS NEW AND CONCLUSION: This study showed that the genetic polymorphisms of CYP3A5*3 and BCRPC421A might explain the variability in the pharmacokinetics of Felodipine in the Chinese population.

Differential blocking action of dihydropyridine Ca2+ antagonists on a T-type Ca2+ channel (alpha1G) expressed in Xenopus oocytes.[Pubmed:15725949]

J Cardiovasc Pharmacol. 2005 Mar;45(3):241-6.

Recent reports show that efonidipine, a dihydropyridine Ca2+ antagonist, has blocking action on T-type Ca2+ channels, which may produce favorable actions on cardiovascular systems. However, the effects of other dihydropyridine Ca2+ antagonists on T-type Ca2+ channels have not been investigated yet. Therefore, in this study, we examined the effects of dihydropyridine compounds clinically used for treatment of hypertension on a T-type Ca2+ channel subtype, alpha1G, expressed in Xenopus oocytes. These effects were compared with those on T-type Ca2+ channel. Rabbit L-type (alpha1Calpha2/deltabeta1a) or rat T-type (alpha1G) Ca2+ channel was expressed in Xenopus oocytes by injection of cRNA for each subunit. The Ba currents through expressed channels were measured by conventional 2-microelectrode voltage-clamp methods. Twelve DHPs (amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, Felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) and mibefradil were tested. Cilnidipine, Felodipine, nifedipine, nilvadipine, minodipine, and nitrendipine had little effect on the T-type channel. The blocks by drugs at 10 microM were less than 10% at a holding potential of -100 mV. The remaining 6 drugs had blocking action on the T-type channel comparable to that on the L-type channel. The blocking actions were also comparable to that by mibefradil. These results show that many dihydropyridine Ca2+ antagonists have blocking action on the alpha1G channel subtype. The action of dihydropyridine Ca2+ antagonists in clinical treatment should be evaluated on the basis of subtype selectivity.

Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes.[Pubmed:10525060]

J Pharmacol Exp Ther. 1999 Nov;291(2):464-73.

Some dihydropyridines (DHPs), such as amlodipine and cilnidipine, have been shown to block not only L-type but also N-type Ca(2+) channels; therefore, DHPs are no longer considered as L-type-specific Ca(2+) channel blockers. However, selectivity of DHPs for Ca(2+) channel subtypes including N-, P/Q-, and R-types are poorly understood. To address this issue at the molecular level, blocking effects of 10 DHPs (nifedipine, nilvadipine, barnidipine, nimodipine, nitrendipine, amlodipine, nicardipine, benidipine, Felodipine, and cilnidipine) on four subtypes of Ca(2+) channels (L-, N-, P/Q-, and R-types) were investigated in the Xenopus oocyte expression system with the use of the two-microelectrode voltage-clamp technique. L-type Ca(2+) channels expressed as alpha(1C)alpha(2)beta(1a) combination were profoundly blocked by all DHPs examined, whereas blocking actions of these DHPs on R-type (alpha(1E)alpha(2)beta(1a)) channels were equally weak. In contrast, 5 of the 10 DHPs (amlodipine, benidipine, cilnidipine, nicardipine, and barnidipine) significantly blocked N-type (alpha(1B)alpha(2)beta(1a)) and P/Q-type (alpha(1A)alpha(2)beta(1a)) Ca(2+) channels. These selectivities of DHPs in blocking Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side effects and adverse effects.

Vascular selectivity of felodipine: experimental pharmacology.[Pubmed:1693715]

J Cardiovasc Pharmacol. 1990;15 Suppl 4:S11-6.

This article presents an overview of experimental studies that illustrate the vascular vs. myocardial selectivity of Felodipine. The aim of our project was to develop a calcium antagonist that would selectively inhibit the activity of the myogenically active smooth muscle of the arterial resistance vessels without causing negative inotropic effects. In vitro, selectivity was tested as the concentration ratio at 50% inhibition of the peak force of paced papillary muscle and of the spontaneous myogenic activity of rat portal vein. The latter preparation has consistently been used as an in vitro model of myogenically active vascular (arterial) smooth muscle. It was found that dihydropyridines display different quantitative structure-activity relationships with regard to vascular and myocardial effects. Felodipine was the first compound synthetized that showed 100-fold vascular selectivity. In the same test system, Ca2+ chelators, La3+, and verapamil lacked selectivity. The high vascular selectivity of Felodipine has been verified in vivo in various hemodynamic experiments. Thus, Felodipine lowers arterial blood pressure due to reduced peripheral resistance without altering cardiac contractility. This is the case in various animal models and applies over a wide range of plasma concentrations whether autonomic nervous control is blocked or not. In contrast, nonselective compounds such as verapamil attenuate myocardial contractility in parallel with a reduction in peripheral resistance.