Validated RP-HPLC method for quantification of felodipine in rabbit plasma: Application in a bioequivalence study.

OBJECTIVE: The aim of present study was to develop a simple, rapid, selective, sensitive and robust reverse phase high performance liquid chromatographic method for quantification of felodipine in rabbit plasma at the wavelength of 360nm. METHOD: Protein was precipitated from rabbit plasma sample by addition of acetonitrile as a vehicle. An isocratic elution of samples was performed on capcell pak C8 DD S5 column (4.6mm×250mm particle size 5µm) column with mobile phase consisting 5mM Phosphate Buffer (pH 4.8 adjusted with dilute ortho-phosphoric acid solution): acetonitrile (25:75:v/v) delivered at flow rate 1.0mLmin-1. RESULT: A good linear response was achieved over the range of 0.25-20.00µgmL-1. LODs and LOQs for felodipine were found to be 0.055 and 0.201µgmL-1, respectively. The method was quantitatively evaluated in terms of linearity, precision, accuracy (recovery), selectivity robustness and stability study as per standard guidelines. The validated RP-HPLC method was successfully applied for the bioavailability studies of felodipine. The pharmacokinetic parameters were calculated for all the investigated drugs in rabbit after single-dose administrations of pure drug and formulation of felodipine. Finally, the obtained results for the application of the proposed RP-HPLC method proved its efficiency to be applied to the therapeutic drug monitoring (TDM) and bioequivalence (BE) studies. CONCLUSION: Thus, developed method is simple, convenient and suitable for the analysis of felodipine in bulk and pharmaceutical formulations.

Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability.

Felodipine (FD) has been widely used in anti-hypertensive treatment. However, it has extremely low aqueous solubility and poor bioavailability. To address these problems, FD hollow microspheres as multiple-unit dosage forms were synthesized by a solvent diffusion evaporation method. Particle size of the hollow microspheres, types of ethylcellulose (EC), amounts of EC, polyvinyl pyrrolidone (PVP) and FD were investigated based on an orthogonal experiment of three factors and three levels. In addition, the release kinetics in vitro and pharmacokinetics in beagle dogs of the optimized FD hollow microspheres was investigated and compared with Plendil (commercial FD sustained-release tablets) as a single-unit dosage form. Results showed that the optimal formulation was composed of EC10 cp:PVP:FD (0.9:0.16:0.36, w/w). The FD hollow microspheres were globular with a hollow structure and have high drug loading (17.69±0.44%) and floating rate (93.82±4.05%) in simulated human gastric fluid after 24h. Pharmacokinetic data showed that FD hollow microspheres exhibited sustained-release behavior and significantly improved relative bioavailability of FD compared with the control. Pharmacodynamic study showed that the FD hollow microspheres could effectively lower blood pressure. Therefore, these findings demonstrated that the hollow microspheres were an effective sustained-release delivery system for FD.

Assessment of improved buccal permeation and bioavailability of felodipine microemulsion-based cross-linked polycarbophil gel.

The oral bioavailability of felodipine (FEL) is very low, i.e., about 15%. This could be due to low water solubility and hepatic first-pass effect. The objective of the present study was to develop FEL microemulsion-based gel, to bypass the first pass effect, for buccal delivery. The optimized FEL microemulsion (OPT-MEF) was used to prepare buccoadhesive gels, with varying concentrations of hydroxypropyl methylcellulose (HPMC) E4M and polycarbophil (PCP), and evaluated. The cross-linking of the PCP gelling agent was done by adjusting the pH with a neutralizing agent, triethanolamine (TEA). The formulations, namely drug suspension, OPT-MEF, microemulsion-based buccal gel containing 1% w/v (MEF-E4M1), 2% w/v (MEF-E4M2), and 3% w/v (MEF-E4M3) of HPMC K4M and 1% w/v (MEF-PCP1), 2% w/v (MEF-PCP2), and 3% w/v (MEF-PCP3) of PCP were prepared and optimized on the basis of ex vivo permeation study, mucoadhesion force, and viscosity. The optimized buccal gel (MEF-PCP1) showed significantly higher (p < 0.01) permeation flux (J = 0.44 ± 0.16 mg/cm2/h), when compared with the drug suspension (J = 0.17 ± 0.14 mg/cm2/h). The permeation enhancement ratio of MEF-PCP1 was found to be 2.59 times higher than that of the aqueous suspension of the drug. The texture profile analysis of MEF-PCP1 was performed which showed spreadability (3.2 mJ), extrudability (151.8 mJ), hardness (13.8 g), and adhesiveness (41.0 g), and results indicated good spreadability and adhesiveness. The rheological study revealed the pseudoplastic flow behavior of MEF-PCP1 buccal gel. The Cmax value 9.21 ± 2.88 µg/ml of MEF-PCP1 gel was found to be significantly higher (P < 0.01) compared to the same dose administered by oral route (Cmax value 3.51 ± 1.74 µg/ml). The relative bioavailability (Fr) of the optimized MEF-PCP1 buccal gel was about 397.39% higher than that of oral route. In conclusion, consistent and effective buccal gel containing optimized FEL-loaded microemulsion, with improved buccal permeation and pharmacokinetic parameters was developed successfully to improve the bioavailability of FEL.

Simultaneous Determination of Felodipine and Metoprolol in Beagle Dog Plasma by Online SPE-LC-MS/MS and Its Application in a Pharmacokinetic Study.

In order to overcome deficiencies for simultaneously determining felodipine (FDP) and metoprolol (MPL) with low recovery and low sensitivity, a new online SPE coupled with the liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method for the simultaneous quantitative determination of FDP and MPL in beagle dog plasma was established. The SPE extraction of FDP and MPL was performed on a Retain PEP Javelin column (10 × 2.1 mm, 5 µm), while the chromatographic separation was achieved on a ZORBAX SB-C18 (50 × 2.1 mm, 3.5 µm) analytical column. Multiple reaction monitoring operated in the positive ion mode was adopted in MS detection, and the precursors to the product ion transition values of m/z 384/338.1, 268/74.2 and 436.2/207.1 were used to measure FDP, MPL and the internal standard (valsartan). The high throughput, accurate and sensitive method for FDP and MPL was validated and applied to the bioavailability research of FDP and MPL in beagle dogs.

Studies on Core-Shell Nanocapsules of Felodipine: In Vitro-In Vivo Evaluations.

The present study aimed for in vitro-in vivo-in silico simulation studies of experimentally designed (32-factorial) Capmul PG-8-cored, Eudragit RSPO-Lutrol F 127 nanocapsules to ferry felodipine using GastroPlus™. The in silico parameter sensitivity analysis for pharmacokinetic parameters was initially assessed to justify the preparation of felodipine-loaded nanocapsules (FLNs) with enhanced solubility to overcome the bioavailability issues of felodipine. The overall integrated desirability ranged between 0.8187 and 0.9488 for three optimized FLNs when analyzed for mean particle size, zeta potential, encapsulation efficiency, and in vitro dissolution parameters. The morphological evaluation (SEM, TEM, and AFM) demonstrated spherical nanoparticles (200-300 nm). Validated LC-MS/MS analysis demonstrated enhanced relative bioavailability (13.37-fold) of optimized FLN as compared to suspension. The simulated regional absorption of the FLN presented significant absorption from the cecum (26.3%) and ascending colon (20.1%) with overall absorption of 67.4% from the GIT tract. Furthermore, in vitro-in vivo correlation demonstrated the Wagner-Nelson method as the preferred model as compared to mechanistic and numerical deconvolution on the basis of least mean absolute prediction error, least standard error of prediction, least mean absolute error, and maximum correlation coefficient (r 2 = 0.920). The study demonstrated enhanced oral absorption of felodipine-loaded nanocapsules, and GastroPlus™ was found to be an efficient simulation tool for in vitro-in vivo-in silico simulations.

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

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 0.05-2.0µgmL-1 for FLD and MET and 0.1-2.0µgmL-1 for RAM with detection limits of 0.013-0.031µgmL-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.

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

Development of a novel starch with a three-dimensional ordered macroporous structure for improving the dissolution rate of felodipine.

In this study, silica nanospheres with different particle sizes were used as hard template for synthesis of a starch with a novel three-dimensional ordered macroporous structure (3DOMTS). As a pharmaceutical adjuvant, 3DOMTS was used to improve the dissolution rate and oral relative bioavailability of water-insoluble drugs. Felodipine (FDP) was chosen as a model drug and was loaded into the 3DOMTS by solvent evaporation. FDP loading into 3DOMTS with different pore sizes was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimeter (DSC), powder X-ray diffractometer (PXRD) and Fourier-Transform Infrared (FTIR). The results obtained showed that FDP was present in the pores in an amorphic or microcrystalline state. The in vitro dissolution results showed that 3DOMTS could effectively improve the dissolution rate of FDP in comparison with commercial common tablets. Pharmacokinetic results indicated that the oral relative bioavailability of self-made FDP-3DOMTS tablets were 184%, showing that 3DOMTS produced a significantly increased oral absorption of FDP. In conclusion, 3DOMTS exhibits the dual potential of improving the dissolution rate of poorly water soluble drugs and the novel filler produced by direct compression technology confirming that 3DOMTS will be useful for many applications in the field of pharmaceutics.

Spectrofluorimetric and micelle-enhanced spectrofluorimetric methods for determination of Felodipine and Nimodipine in pharmaceutical preparations and human plasma.

Rapid, simple and sensitive two spectrofluorimetric methods have been developed for determination of Felodipine (FLD) and Nimodipine (NDP). The first method is based on measuring the native fluorescence of either Felodipine or Nimodipine at 426 nm after excitation at 385 nm. The fluorescence intensity-concentration plots of Felodipine and Nimodipine were rectilinear over the concentration ranges (0.2-3.0) and (0.5-4.0) µg ml(-1), respectively. The second method is based on measuring the fluorescence intensity of the studied drugs in micellar media (0.3% Tween-80) at λex=385 nm and λem=423 nm. In the presence of 0.3% Tween-80, about 1.6-fold and 2.1-fold enhancement can be achieved in the relative fluorescence intensity (RFI) of Felodipine and Nimodipine, respectively. The fluorescence intensity-concentration plots of Felodipine and Nimodipine with Tween-80 were rectilinear over the concentration ranges (0.05-4.0) and (0.1-4.0) µg ml(-1), respectively with determination coefficients (r(2)) of 0.9981 and 0.9990, and limit of quantitation of 0.05 and 0.027µg ml(-1) for FLD and NDP, respectively. The proposed methods were validated according to ICH guidelines and have been successfully applied to the analysis of these drugs in their commercial tablets with high accuracy (97.6-98.8±0.50-1.42%, n=5). The high sensitivity of micellar method permits its application for determination of the cited drugs in spiked human plasma with % recovery (91.9-106.6±0.66-1.7%, n=6).

In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction.

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.

In vitro/in vivo evaluation of felodipine micropowders prepared by the wet-milling process combined with different solidification methods.

In order to improve the in vitro dissolution rate and in vivo oral bioavailability of the poorly water soluble drug, felodipine (FELO), the wet-milling process was employed involving co-grinding with HPMC E5 and the in vitro release rate as investigated. After solidification by spray drying or freeze drying, the microsized powders were characterized in terms of their size, morphology, and in vitro dissolution rate. The oral bioavailability of this dry powder for suspension was evaluated in rats. After milling with 8% HPMC E5 and freeze drying, the powder mixture had an average particle size of 2.249 ± 1.497 µm and displayed an excellent dissolution rate of up to 93.2% within 10 minutes. DSC and PXRD investigations confirmed the absence of any crystal transformation during the wet-milling process. Using two different solidification methods, powders were stable for 6 months with regard to their in vitro dissolution rate. Significantly improved bioavailability was obtained for the wet-milled suspension before solidification and freeze dried powders with 6.8- (p < 0.001) and 3.6-fold (p < 0.01) increases, respectively, compared with that of the un-milled FELO. Also, no marked difference (p > 0.05) in bioavailability was seen for the spray dried powders. These effects suggest that the solidification method plays an important role in modifying the bioavailability of FELO after wet milling. Consequently, wet-milling is an effective technique to enhance the bioavailability of FELO and to maintain these benefits, freeze-drying is a feasible approach to solidifying the wet-milled suspension for industrial applications.

Preparation and in vitro/in vivo evaluation of felodipine nanosuspension.

The purpose of this study was to develop a nanosuspension of a poorly soluble drug felodipine by nanoprecipitation to achieve superior in vitro dissolution and high oral absorption in vivo in rats. Felodipine nanosuspensions were prepared by precipitation with ultrasonication method using polyvinyl alcohol (PVA) and hydroxy propyl methyl cellulose (HPMC) as stabilizers. The particle size of nanosuspension with PVA was 60-200 nm, while with HPMC is 300-410 nm. The in vitro dissolution and pharmacokinetics of optimized nanosuspensions were studied after oral administration in male wistar rats. The results showed significant improvement during in vitro dissolution and in vivo plasma level. Dissolution studies of lyophillised nanoparticles showed that up to 93.0 % dissolved in 2 h. In the in vivo evaluation, nanosuspension exhibited significant increase in AUC0-24, C max and decrease in t max. The findings revealed that particle size reduction can influence felodipine absorption in gastrointestinal tract and nanosuspension can enhance oral bioavailability of felodipine in rats.

Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using felodipine and hesperetin in combination in Wistar rats and everted rat gut sacs in vitro.

The effects of hesperetin on the pharmacokinetics and the role of P-glycoprotein (P-gp) in the transport of felodipine were investigated in rats and in vitro. Felodipine was administered orally (10 mg/kg) without or with hesperetin (25, 50 and 100 mg/kg) to rats for 15 consecutive days. Blood samples were collected at different time intervals on 1(st) day in single dose pharmacokinetic study (SDS) and on 15(th) day in multiple dose pharmacokinetic study (MDS). The area under the plasma concentration-time curve (AUC0-∞ ) and the peak plasma concentration (Cmax ) of felodipine were dose-dependently increased in SDS and MDS with hesperetin compared to control ( p < 0.001). The half-life (t1/2 ) and mean residence time was longer than the control group in both studies. The role of P-gp determined using everted rat gut sacs in vitro by incubating felodipine with or without hesperetin and verapamil (typical P-gp and CYP3A4 inhibitor). The in vitro experiments revealed that the verapamil and hesperetin increased the intestinal absorption of felodipine (p < 0.01). Concurrent use of hesperetin dramatically altered the pharmacokinetics of felodipine leading to an increase in systemic exposure. The likely mechanism is inhibition of CYP3A4-mediated first-pass metabolism and P-gp in the intestine and the liver.

Validated LC-ESI-MS/MS method for simultaneous quantitation of felodipine and metoprolol in rat plasma: application to a pharmacokinetic study in rats.

A highly sensitive and specific LC-ESI-MS/MS method has been developed and validated for simultaneous quantification of felodipine (FDP) and metoprolol (MPL) in rat plasma (50 µL) using phenacetin as an internal standard (IS) as per the FDA guidelines. Liquid-liquid extraction method was used to extract the analytes and IS from rat plasma. The chromatographic resolution of FDP, MPL and IS was achieved with a mobile phase consisting of 0.2% formic acid in water-acetonitrile (25:75, v/v) with a time program flow gradient on a C18 column. The total chromatographic run time was 4.0 min and the elution of FDP, MPL and IS occurred at 1.05, 2.59 and 1.65 min, respectively. A linear response function was established for the range of concentrations 0.59-1148 and 0.53-991 ng/mL for FDP and MPL, respectively, in rat plasma. The intra- and inter-day accuracy and precision values for FDP and MPL met the acceptance as per FDA guidelines. FDP and MPL were stable in battery of stability studies viz., bench-top, auto-sampler and freeze-thaw cycles. The validated assay was applied to a pharmacokinetic study in rats.

Development of a high-performance liquid chromatography method for simultaneous determination of pioglitazone and felodipine in pig serum: application to pharmacokinetic study.

A simple and sensitive high-performance liquid chromatographic method was developed and validated for simultaneous estimation of pioglitazone and felodipine in pig serum. The present method consists of protein precipitation, extraction of analytes from pig serum into dichloromethane and separation using reversed-phase C(18) column. Nitrendipine was used as an internal standard and the eluent was monitored by UV detector at 240 nm. The mobile phase used was acetonitrile and 50 mm ammonium acetate buffer at a flow rate of 1 mL/min. The retention times for pioglitazone, felodipine and nitrendipine were found to be 5.12, 10.53 and 7.14 min, respectively. The intraday and inter-day coefficient of variation and percent error values of assay method were less than 7% and mean recovery was more than 94% for each analyte, and the method was found to be precise, accurate and specific during study. The method was successfully applied for pharmacokinetic study of pioglitazone and felodipine from bioadhesive buccal tablet after buccal administration to pigs. The C(Max) , T(Max) , and AUC(0-24) of pioglitazone and felodipine from buccal tablet were found to be 394.6 ng/mL, 5.6 h, 2624.2 ng h/mL and 44.4 ng/mL, 5.5 h, 275.8 ng h/mL, respectively.

Simultaneous determination of nitrendipine and one of its metabolites in plasma samples by gas chromatography with electron-capture detection.

A sensitive method for GC-ECD simultaneous determination of nitrendipine and its pyridine metabolite M1 in human plasma is described. Felodipine was used as the internal standard. The plasma samples were extracted with toluene. One microlitre of the extract was injected onto the capillary column (polymethylsiloxane) and measured with electron-capture detector. The developed method showed to be linear over the range 0.25-70 for nitrendipine and 0.3-61 ng/ml for its metabolite M1 with an inter-day and intra-day precision in terms of R.S.D. lower than 8% except the concentrations near lowest limit of quantification (LLOQ) (<11% R.S.D.). The LLOQ for nitrendipine was 0.25 and 0.3 ng/ml for its metabolite, respectively. The analytical recovery was 94% for nitrendipine and 89% for its pyridine metabolite M1. This GC-ECD method was developed for being used in clinical pharmacokinetic studies.

[Preparation of transdermal drug delivery system of felodipine-metoprolol and its bioavailability in rabbits].

To prepare transdermal drug delivery system (TDDS) of felodipine and metoprolol and to study its pharmaceutical characteristics, pharmacokinetics and bioavailability in rabbits, an HPLC assay was established for the simultaneous determination of felodipine and metoprolol in the permeation receptor and patch. The permeation rate and permeation mechanism of felodipine-metoprolol-TDDS through rabbit skin in vitro was examined. The determination of drug content, the examination of content uniformity and stability of the TDDS were carried out. GC-ECD assays were established for the determination of felodipine and metoprolol in plasma separately and then employed to study the pharmacokinetics and bioavailability of felodipine and metoprolol after a single dose of oral or transdermal administration in rabbits. The results indicated that the permeation of flodipine and metoprolol from the patch through excised rabbit skin exhibited zero-order kinetic characteristics. The determination of drug content and the quality control of content uniformity of the patch accorded with Pharmacopoeia of the People's Republic of China of 2005 edition and the pharmaceutical characterization showed good stability. In contrast to oral delivery, relatively constant, sustained blood concentration with minimal fluctuation and prolonged peak time were observed over a long period after transdermal administration. The relative bioavailability of felodipine and metoprolol were 275.37% and 189.76% versus oral administration respectively. It was evident that the felodipine-metoprolol-TDDS exhibited good controlled release properties that satisfied the demands of original design that enhancing bioavailability and maintaining appropriate blood levels for a prolonged time without adverse effects associated with frequent oral administration.

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

BACKGROUND: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear. OBJECTIVE: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine. DESIGN: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximately 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments. RESULTS: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol . h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol . h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol . h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively]. CONCLUSION: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.

Sympatho-excitatory responses to once-daily dihydropyridines in young versus older hypertensive patients: amlodipine versus felodipine extended release.

BACKGROUND: Once-daily dihydropyridines exert both indirect sympatho-excitatory and direct central sympatho-inhibitory effects. Age may affect this balance by influencing blood pressure (BP) or renin responses. METHODS: We evaluated BP, sympathetic and cardiac responses after the first dose and after 8 weeks of treatment with placebo, amlodipine 5 mg/day or felodipine extended release (ER) 5 mg/day in 29 young (22-50 years) versus 37 older (60-77 years) hypertensive patients, using a double-blind, parallel group design. RESULTS: In the young group, neither dihydropyridine dose decreased BP after the first dose and both caused decreases by 5-10 mmHg after chronic treatment. In the older group, felodipine ER decreased BP rapidly and amlodipine more gradually, and after chronic treatment, systolic BP decreased by 20-25 mmHg. Felodipine ER increased the heart rate by 5-10 bpm after the first dose in both age groups and caused persistent increases in the cardiac index (by 0.2 l/min per square metre) and the ejection fraction only in the older group. Amlodipine did not affect cardiac function in the young, and with chronic dosing decreased the heart rate by 3-5 bpm and the cardiac index by 0.2 l/min per square metre in the older group. In the young hypertensive patients, both dihydropyridines increased plasma norepinephrine (NE) after chronic dosing, with little effect after the first dose. In contrast, in the older group felodipine ER increased plasma NE after the first dose but not with chronic dosing, whereas amlodipine had no effect after the first dose, and after chronic dosing tended to decrease plasma NE. CONCLUSION: We conclude that age is a major determinant not only of the BP but also of the cardiac and sympathetic responses to once-daily dihydropyridines.

Impact of the intragastric location of extended release tablets on food interactions.

Gastrointestinal motility and transport as well as concomitant food intake are factors that are known to influence pharmacokinetics derived after intake of extended release dosage forms. However, the mechanisms behind these influencing factors are mostly unknown. In this study the gastrointestinal transit and the in vivo drug release of magnetically labelled extended release tablets containing felodipine were monitored together with the drug absorption phase of pharmacokinetics under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring. It was found that the in vivo drug release profiles of the tablets compared well under fasting and fed conditions. However, the plasma concentration profiles were strongly influenced by concomitant food intake. This could be attributed to elongated residence of the tablets in proximal parts of the stomach, resulting in delayed drug absorption and the occurrence of late high plasma peak concentrations. The lag time until the first appearance of felodipine in plasma and the residence time of the tablets in the proximal stomach, were found to be directly correlated. The study shows that increased plasma peak drug concentrations after intake of extended release formulations together with food can be explained by poor mixing in the proximal part of the stomach and are not necessarily due to failure of the formulation to control drug release (dose dumping).