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Reza Tabrizchi - One of the best experts on this subject based on the ideXlab platform.
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regulation of intracellular ca2 by 8 bromoguanosine 3 5 cyclic monophosphate Felodipine and ryanodine in rat caudal artery
European Journal of Pharmacology, 1996Co-Authors: Suyin Lum A Min, Reza TabrizchiAbstract:Abstract 45Ca2+ efflux in isolated rat caudal artery was measured in the absence and presence of 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP), Felodipine or ryanodine after stimulation of α1-adrenoceptors. The objectives of this study were to identify the mechanisms of action of 8-Br-cGMP, Felodipine and ryanodine in a vascular resistance vessel. 8-Br-cGMP and ryanodine but not Felodipine increased basal 45Ca2+ efflux. Phenylephrine-induced 45Ca2+ efflux was reduced by all three antagonists. The results of this study demonstrate that, (1) 8-Br-cGMP-mediated relaxation is affected in part by an increased extrusion of intracellular Ca2+ and/or inhibition of intracellular Ca2+ release, (2) the Ca2+-channel antagonist, Felodipine, impairs intracellular Ca2+ release and (3) ryanodine reduced phenylephrine-induced Ca2+ efflux by depleting intracellular Ca2+ stores.
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effects of 8 bromoguanosine 3 5 cyclic monophosphate on phenylephrine induced phosphatidylinositol hydrolysis and contraction in rat caudal artery
British Journal of Pharmacology, 1995Co-Authors: Suyin Lum A Min, Reza TabrizchiAbstract:1. The effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-bromo-cyclic GMP) on phenylephrine-induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of Felodipine, a dihydropyridine Ca2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor-mediated signal transduction in vascular smooth muscle. 2. Phenylephrine induced a concentration-dependent increase in PI hydrolysis that reached a maximum at 10 microM phenylephrine. Pre-incubation with Felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca2+ (2 mM ethylene glycol-bis(beta-amino-ethyl ether) N, N, N', N'-tetraacetic acid (EGTA)) blocked phenylephrine-induced PI hydrolysis, but did not affect basal turnover. In contrast, 8-bromo-cyclic GMP (10 microM) did not affect phenylephrine-induced PI hydrolysis, nor did it affect basal turnover. 3. Phenylephrine induced concentration-dependent contractions that were inhibited by each of 8-bromo-cyclic GMP (10 microM), Felodipine (1 nM and 10 nM) and ryanodine (3 microM and 10 microM). In addition, removal of Ca2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine. 4. Phenylephrine-induced contractions were not further affected by Felodipine and 8-bromo-cyclic GMP applied concomitantly than by equivalent concentrations of Felodipine alone. However, ryanodine and 8-bromo-cyclic GMP applied together significantly inhibited phenylephrine-induced contractions in comparison to ryanodine alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Lynne S Taylor - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the crystal growth rate of Felodipine polymorphs in the presence and absence of additives as a function of temperature
Crystal Growth & Design, 2013Co-Authors: Umesh S Kestur, Lynne S TaylorAbstract:The purpose of the present study was to compare the effect of temperature and a polymeric additive, poly(vinyl pyrrolidone) (PVP), on the crystal growth rate of two polymorphs of Felodipine from amorphous samples. Comparing the growth rates of the two polymorphs in the presence of PVP should provide mechanistic information on whether PVP inhibits crystal growth of Felodipine by interacting at the crystal surface of Felodipine or in the amorphous regions. Optical microscopy was used to measure the growth rates at various temperatures in the range of 18–100 °C for the form I polymorph and 40–100 °C for the form II polymorph. Both surface and bulk growth rates for the form I polymorph were evaluated, while for the form II polymorph, only the bulk growth rate could be studied. No difference in the growth rate between surface and bulk crystals of form I was observed at higher temperatures (>70 °C). However, below 65 °C the surface crystal growth rate was faster than the bulk crystal growth rate. Another mode o...
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quantitative analysis of the inhibitory effect of hpmc on Felodipine crystallization kinetics using population balance modeling
CrystEngComm, 2013Co-Authors: Kaoutar Abbou Oucherif, Shweta A Raina, Lynne S Taylor, J D LitsterAbstract:In the present paper, the effect of the polymer additive, hydroxypropylmethyl cellulose (HPMC), on inhibiting the nucleation and growth of Felodipine from supersaturated aqueous solutions was investigated. To characterize the growth and nucleation kinetics, seeded and unseeded desupersaturation experiments were carried out, respectively. A mathematical model for the batch crystallization of Felodipine was constructed by using empirical expressions for nucleation and growth, a population balance equation, and a material balance. An optimization algorithm was employed to obtain the kinetic parameters in the nucleation and growth expressions by fitting the simulated results to the experimental data. Population balance modeling successfully allowed for the decoupling of the separate effect of HPMC on the nucleation and growth rates. In both the absence and presence of polymer, the growth mechanism of Felodipine was determined to be intermediate between mass diffusion and surface integration controlled growth. HPMC was able to inhibit nucleation and growth at very low polymer concentrations (0.2 μg mL−1). However, the inhibitory impact was much greater on nucleation as opposed to growth. At a concentration of 3.5 μg mL−1, HPMC was found to decrease Felodipine nucleation by up to eight orders of magnitude while it only decreased the rate of crystal growth by a factor of two. Furthermore, at high concentrations, the inhibitory impact of HPMC on growth reached a plateau and any further increases in polymer concentration were ineffective.
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influence of particle size on the crystallization kinetics of amorphous Felodipine powders
Powder Technology, 2013Co-Authors: Umesh S Kestur, David E Alonzo, Igor Ivanesivic, Lynne S TaylorAbstract:Abstract The goal of this study was to investigate the influence of particle size on the crystallization kinetics of amorphous Felodipine powders stored below the glass transition temperature and to evaluate the role of surface versus bulk crystallization in influencing the kinetic profiles. Raman spectroscopy and powder X-ray diffraction (PXRD) were used to monitor the crystallization of different particle size fractions of pure amorphous Felodipine and solid dispersions containing 3 wt.% polyvinyl pyrrolidone (PVP) stored at 30 °C. Optical microscopy was employed to measure surface and bulk growth rates of Felodipine in the absence and presence of PVP at 30 °C. Solution concentration-time profiles for the various samples prior to and after crystallization were also measured. The growth rate of Felodipine from the free surface was approximately 6 times faster than from the bulk in the absence of any polymer while the ratio of the surface to bulk growth rates was 23 in the presence of PVP. The overall crystallization rates of the amorphous powders were particle size dependent with smaller particle sizes crystallizing faster. Felodipine alone crystallized within 7 days. However, in the presence of the polymer, crystallization was retarded and was incomplete after 6 months. For the polymer-containing powders, biphasic crystallization was observed whereby rapid initial crystallization (50–60 days) was followed by a much slower rate over the remaining time period. The initial rapid crystallization was attributed to a faster rate of surface growth. The dissolution profiles of the different powders were dependent on both the particle size and the extent of crystallinity, with the level of supersaturation achieved varying considerably.
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effects of moisture on the growth rate of Felodipine crystals in the presence and absence of polymers
Crystal Growth & Design, 2010Co-Authors: Matthew J Jackson, Alfred C F Rumondor, Lynne S TaylorAbstract:The purpose of this study was to examine how moisture affects the growth rate of Felodipine crystals from amorphous systems. Amorphous Felodipine films with 0−10% w/w poly(vinylpyrrolidone) (PVP) or hypromellose acetate succinate (HPMCAS) were prepared by spin coating and stored at room temperature at different relative humidities (RHs). Linear growth rates were determined using optical microscopy. Crystals grown from Felodipine alone had the fastest growth rate under all conditions. An approximately log−linear relationship between crystal growth rate and storage RH was observed between 13% and 80% RH. Above 80% RH, an abrupt 15−40-fold increase in growth rate occurred, producing crystals of a different morphology. Polymeric additives decreased crystal growth rates, more so with increasing polymer concentration. Growth rates from PVP-containing films increased with increasing storage RH, but thosefor HPMCAS systems did not. Below 52% RH, PVP was the better growth inhibitor; above 64% RH, HPMCAS inhibited ...
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evaluation of drug polymer miscibility in amorphous solid dispersion systems
Pharmaceutical Research, 2009Co-Authors: Alfred C F Rumondor, Igor Ivanisevic, Simon Bates, David E Alonzo, Lynne S TaylorAbstract:Purpose To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely Felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and Felodipine-poly(acrylic acid) (PAA).
David G. Bailey - One of the best experts on this subject based on the ideXlab platform.
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bergamottin lime juice and red wine as inhibitors of cytochrome p450 3a4 activity comparison with grapefruit juice
Clinical Pharmacology & Therapeutics, 2003Co-Authors: David G. Bailey, George K Dresser, John R. BendAbstract:Objectives: Our objective was to assess the importance of bergamottin in drug interactions through comparisons between grapefruit juice and lime juice and the potential for drug interactions with red wine. Methods: Bergamottin content and in vitro reversible/irreversible inhibition of cytochrome P450 (CYP) 3A4 monooxygenase activities were determined for grapefruit and lime juices. The oral pharmacokinetics of Felodipine and its primary metabolite (dehydroFelodipine) were determined with 250 mL of grapefruit juice, one quarter–strength lime juice, red wine, or water in a randomized crossover study. Results: Bergamottin concentrations in grapefruit and lime juices were 25 and 100 μmol/L, respectively. For reversible inhibition, log volume-residual CYP3A4 activity relationships for grapefruit and lime juices had negative linear slopes that were parallel. The curve for grapefruit juice was 4.0-fold right-shifted, as compared with that for lime juice. For irreversible inhibition, the curves for grapefruit and lime juices were 4.0- and 1.4-fold left-shifted, as compared with those for reversible inhibition, respectively. Grapefruit juice increased the mean Felodipine area under the plasma concentration-time curve (AUC) (mean ± SE, 55 ± 9 nmol · h/L versus 29 ± 6 nmol · h/L; P < .05) and the plasma peak drug concentration (16 ± 3 nmol/L versus 8 ± 2 nmol/L, P < .05) and decreased the dehydroFelodipine/Felodipine AUC ratio compared with those of water. One quarter–strength lime juice did not alter mean values. However, the changes in individual Felodipine AUC after grapefruit juice and lime juice correlated (r2 = 0.95) with a low slope (0.36). One quarter–strength lime juice more than doubled Felodipine AUC and plasma peak drug concentration in 2 subjects. Red wine prolonged mean Felodipine time to plasma peak drug concentration. Felodipine concentrations were low and peaked abruptly in 4 subjects. Adverse effects occurred in 1 subject. Conclusions: Bergamottin and reversible inhibition are not the primary substance and mechanism responsible for inhibition of CYP3A4 activity clinically. Red wine can cause dose dumping of extended-release Felodipine in certain individuals. Clinical Pharmacology & Therapeutics (2003) 73, 529–537; doi: 10.1016/S0009-9236(03)00051-1
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grapefruit juice Felodipine interaction in the elderly
Clinical Pharmacology & Therapeutics, 2000Co-Authors: George K Dresser, David G. Bailey, George S CarruthersAbstract:Background Grapefruit juice can increase the oral bioavailability of a broad range of medications. This interaction has not been assessed in the elderly. Methods Twelve healthy elderly people (70 to 83 years of age) were administered 5 mg Felodipine extended release with 250 mL grapefruit juice or water in a single-dose study. Subsequently, 6 of these people received 2.5 mg Felodipine for 2 days, followed by 5 mg Felodipine for 6 days with 250 mL grapefruit juice or water in a steady-state study. Plasma concentrations of Felodipine and dehydroFelodipine metabolite, blood pressure, and heart rate were measured over 24 hours after single and final steady-state dose. Results Mean Felodipine area under the curve and maximum concentration were 2.9-fold and 4.0-fold greater, respectively, with grapefruit juice in both studies. Interindividual variability in the extent of the interaction was high. Felodipine apparent elimination half-life was not altered. DehydroFelodipine area under the curve and maximum concentration were increased and dehydroFelodipine/Felodipine area under the curve ratio was reduced. Systolic and diastolic blood pressures were lower with grapefruit juice in the single-dose study, whereas they were not different between treatments in the steady-state study. Curvilinear relationships existed between plasma Felodipine concentration and changes in systolic and diastolic blood pressures. Heart rates were higher with grapefruit juice in both studies; however, this effect was greater and more prolonged at steady state. Conclusions A normal dietary amount of grapefruit juice produced a pronounced, unpredictable, and sustained pharmacokinetic interaction with Felodipine by reducing its presystemic metabolism in the elderly. The different blood pressure results between the studies can be explained by Felodipine concentration-blood pressure response relationships. The elderly should be particularly cautioned about concomitant grapefruit juice and Felodipine ingestion. Clinical Pharmacology & Therapeutics (2000) 68, 28–34; doi: 10.1067/mcp.2000.107524
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grapefruit juice Felodipine interaction effect of naringin and 6 7 dihydroxybergamottin in humans
Clinical Pharmacology & Therapeutics, 1998Co-Authors: David G. Bailey, Claudio Munoz, John R. Bend, John H. Kreeft, David J. FreemanAbstract:Objective To test whether naringin or 6′,7′-dihydroxybergamottin is a major active substance in grape-fruit juice-Felodipine interaction in humans. Methods Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6′,7′-dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral Felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study. Results The amounts of naringin and 6′,7′-dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of Felodipine were higher with supernatant fraction (81 nmol · h/L and 20 nmol/L), particulate fraction (117 nmol · h/L and 24 nmol/L), and grapefruit juice (130 nmol · h/L and 33 nmol/L) compared with water (53 nmol · h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for Felodipine and a similar Cmax of Felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydroFelodipine nor decreased the AUC ratio of dehydroFelodipine to Felodipine compared with water. Individually the supernatant fraction consistently produced lower Felodipine AUC and Cmax compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction. Conclusions Naringin and 6′,7′-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice-Felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsibile for inhibition of cytochrome P450 3A4 in humans. Clinical Pharmacology & Therapeutics (1998) 64, 248–256; doi:
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grapefruit juice increases Felodipine oral availability in humans by decreasing intestinal cyp3a protein expression
Journal of Clinical Investigation, 1997Co-Authors: Kenneth S Lown, David G. Bailey, Robert J Fontana, Srinivas K Janardan, Constance H Adair, Laurie A Fortlage, Morton B Brown, Wensheng Guo, Paul B WatkinsAbstract:The increase in oral availability of Felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral Felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when Felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral Felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.
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erythromycin Felodipine interaction magnitude mechanism and comparison with grapefruit juice
Clinical Pharmacology & Therapeutics, 1996Co-Authors: David G. Bailey, John R. Bend, Lan T. Tran, Malcolm J O Arnold, David J SpenceAbstract:Objective To investigate a potentially marked effect by erythromycin on Felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and Felodipine. Methods Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of Felodipine, the primary metabolite dehydroFelodipine, and the major secondary derivative M3 metabolite were studied. Results Compared with water, erythromycin produced severalfold higher Felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentrations (Cmax), and apparent elimination half-life (t12); however, the effect was variable among individuals. Erythromycin augmented dehydroFelodipine AUC, Cmax, and t12 but decreased dehydroFelodipine/Felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydroFelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong Felodipine or dehydroFelodipine t12. Individually, Felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative Felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative Felodipine Cmax but not with relative Felodipine t12, suggesting Felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. Conclusions Erythromycin produced an important pharmacokinetic interaction with Felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced Felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall. Clinical Pharmacology & Therapeutics (1996) 60, 25–33; doi:
Suyin Lum A Min - One of the best experts on this subject based on the ideXlab platform.
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regulation of intracellular ca2 by 8 bromoguanosine 3 5 cyclic monophosphate Felodipine and ryanodine in rat caudal artery
European Journal of Pharmacology, 1996Co-Authors: Suyin Lum A Min, Reza TabrizchiAbstract:Abstract 45Ca2+ efflux in isolated rat caudal artery was measured in the absence and presence of 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP), Felodipine or ryanodine after stimulation of α1-adrenoceptors. The objectives of this study were to identify the mechanisms of action of 8-Br-cGMP, Felodipine and ryanodine in a vascular resistance vessel. 8-Br-cGMP and ryanodine but not Felodipine increased basal 45Ca2+ efflux. Phenylephrine-induced 45Ca2+ efflux was reduced by all three antagonists. The results of this study demonstrate that, (1) 8-Br-cGMP-mediated relaxation is affected in part by an increased extrusion of intracellular Ca2+ and/or inhibition of intracellular Ca2+ release, (2) the Ca2+-channel antagonist, Felodipine, impairs intracellular Ca2+ release and (3) ryanodine reduced phenylephrine-induced Ca2+ efflux by depleting intracellular Ca2+ stores.
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effects of 8 bromoguanosine 3 5 cyclic monophosphate on phenylephrine induced phosphatidylinositol hydrolysis and contraction in rat caudal artery
British Journal of Pharmacology, 1995Co-Authors: Suyin Lum A Min, Reza TabrizchiAbstract:1. The effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-bromo-cyclic GMP) on phenylephrine-induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of Felodipine, a dihydropyridine Ca2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor-mediated signal transduction in vascular smooth muscle. 2. Phenylephrine induced a concentration-dependent increase in PI hydrolysis that reached a maximum at 10 microM phenylephrine. Pre-incubation with Felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca2+ (2 mM ethylene glycol-bis(beta-amino-ethyl ether) N, N, N', N'-tetraacetic acid (EGTA)) blocked phenylephrine-induced PI hydrolysis, but did not affect basal turnover. In contrast, 8-bromo-cyclic GMP (10 microM) did not affect phenylephrine-induced PI hydrolysis, nor did it affect basal turnover. 3. Phenylephrine induced concentration-dependent contractions that were inhibited by each of 8-bromo-cyclic GMP (10 microM), Felodipine (1 nM and 10 nM) and ryanodine (3 microM and 10 microM). In addition, removal of Ca2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine. 4. Phenylephrine-induced contractions were not further affected by Felodipine and 8-bromo-cyclic GMP applied concomitantly than by equivalent concentrations of Felodipine alone. However, ryanodine and 8-bromo-cyclic GMP applied together significantly inhibited phenylephrine-induced contractions in comparison to ryanodine alone.(ABSTRACT TRUNCATED AT 250 WORDS)
John R. Bend - One of the best experts on this subject based on the ideXlab platform.
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bergamottin lime juice and red wine as inhibitors of cytochrome p450 3a4 activity comparison with grapefruit juice
Clinical Pharmacology & Therapeutics, 2003Co-Authors: David G. Bailey, George K Dresser, John R. BendAbstract:Objectives: Our objective was to assess the importance of bergamottin in drug interactions through comparisons between grapefruit juice and lime juice and the potential for drug interactions with red wine. Methods: Bergamottin content and in vitro reversible/irreversible inhibition of cytochrome P450 (CYP) 3A4 monooxygenase activities were determined for grapefruit and lime juices. The oral pharmacokinetics of Felodipine and its primary metabolite (dehydroFelodipine) were determined with 250 mL of grapefruit juice, one quarter–strength lime juice, red wine, or water in a randomized crossover study. Results: Bergamottin concentrations in grapefruit and lime juices were 25 and 100 μmol/L, respectively. For reversible inhibition, log volume-residual CYP3A4 activity relationships for grapefruit and lime juices had negative linear slopes that were parallel. The curve for grapefruit juice was 4.0-fold right-shifted, as compared with that for lime juice. For irreversible inhibition, the curves for grapefruit and lime juices were 4.0- and 1.4-fold left-shifted, as compared with those for reversible inhibition, respectively. Grapefruit juice increased the mean Felodipine area under the plasma concentration-time curve (AUC) (mean ± SE, 55 ± 9 nmol · h/L versus 29 ± 6 nmol · h/L; P < .05) and the plasma peak drug concentration (16 ± 3 nmol/L versus 8 ± 2 nmol/L, P < .05) and decreased the dehydroFelodipine/Felodipine AUC ratio compared with those of water. One quarter–strength lime juice did not alter mean values. However, the changes in individual Felodipine AUC after grapefruit juice and lime juice correlated (r2 = 0.95) with a low slope (0.36). One quarter–strength lime juice more than doubled Felodipine AUC and plasma peak drug concentration in 2 subjects. Red wine prolonged mean Felodipine time to plasma peak drug concentration. Felodipine concentrations were low and peaked abruptly in 4 subjects. Adverse effects occurred in 1 subject. Conclusions: Bergamottin and reversible inhibition are not the primary substance and mechanism responsible for inhibition of CYP3A4 activity clinically. Red wine can cause dose dumping of extended-release Felodipine in certain individuals. Clinical Pharmacology & Therapeutics (2003) 73, 529–537; doi: 10.1016/S0009-9236(03)00051-1
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grapefruit juice Felodipine interaction effect of naringin and 6 7 dihydroxybergamottin in humans
Clinical Pharmacology & Therapeutics, 1998Co-Authors: David G. Bailey, Claudio Munoz, John R. Bend, John H. Kreeft, David J. FreemanAbstract:Objective To test whether naringin or 6′,7′-dihydroxybergamottin is a major active substance in grape-fruit juice-Felodipine interaction in humans. Methods Grapefruit juice was separated by means of centrifugation and filtration into supernatant and particulate fractions, which were then assayed for naringin and 6′,7′-dihydroxybergamottin. The effect of these fractions, grapefruit juice (containing comparable amounts of both fractions), and water on the pharmacokinetics of oral Felodipine were assessed in 12 healthy men in a randomized, 4-way crossover study. Results The amounts of naringin and 6′,7′-dihydroxybergamottin in the supernatant fraction (148 mg and 1.85 mg) were greater than in the particulate fraction (7 mg and 0.60 mg). The area under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of Felodipine were higher with supernatant fraction (81 nmol · h/L and 20 nmol/L), particulate fraction (117 nmol · h/L and 24 nmol/L), and grapefruit juice (130 nmol · h/L and 33 nmol/L) compared with water (53 nmol · h/L and 11 nmol/L). However, the supernatant fraction had a lower AUC for Felodipine and a similar Cmax of Felodipine relative to the particulate fraction. The supernatant fraction neither augmented the AUC of the primary metabolite dehydroFelodipine nor decreased the AUC ratio of dehydroFelodipine to Felodipine compared with water. Individually the supernatant fraction consistently produced lower Felodipine AUC and Cmax compared with grapefruit juice. In contrast, the particulate fraction had values ranging from more than grapefruit juice to less than supernatant fraction. Conclusions Naringin and 6′,7′-dihydroxybergamottin are not the major active ingredients, although they may contribute to the grapefruit juice-Felodipine interaction. The variable effect with the particulate fraction may result from erratic bioavailability of unidentified primary active substances. The findings show the importance of in vivo testing to determine the ingredients in grapefruit juice responsibile for inhibition of cytochrome P450 3A4 in humans. Clinical Pharmacology & Therapeutics (1998) 64, 248–256; doi:
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erythromycin Felodipine interaction magnitude mechanism and comparison with grapefruit juice
Clinical Pharmacology & Therapeutics, 1996Co-Authors: David G. Bailey, John R. Bend, Lan T. Tran, Malcolm J O Arnold, David J SpenceAbstract:Objective To investigate a potentially marked effect by erythromycin on Felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and Felodipine. Methods Felodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of Felodipine, the primary metabolite dehydroFelodipine, and the major secondary derivative M3 metabolite were studied. Results Compared with water, erythromycin produced severalfold higher Felodipine area under the plasma drug concentration-time profile (AUC), plasma peak drug concentrations (Cmax), and apparent elimination half-life (t12); however, the effect was variable among individuals. Erythromycin augmented dehydroFelodipine AUC, Cmax, and t12 but decreased dehydroFelodipine/Felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydroFelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong Felodipine or dehydroFelodipine t12. Individually, Felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative Felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative Felodipine Cmax but not with relative Felodipine t12, suggesting Felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination. Conclusions Erythromycin produced an important pharmacokinetic interaction with Felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced Felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall. Clinical Pharmacology & Therapeutics (1996) 60, 25–33; doi:
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grapefruit juice Felodipine interaction reproducibility and characterization with the extended release drug formulation
British Journal of Clinical Pharmacology, 1995Co-Authors: David G. Bailey, J M O Arnold, John R. Bend, L T Tran, J D SpenceAbstract:1. Felodipine 10 mg extended release was administered with 250 ml regular-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. The pharmacokinetics of Felodipine and primary oxidative metabolite, dehydroFelodipine, were evaluated. 2. Initial grapefruit juice treatment increased Felodipine AUC (mean +/- s.d.; 56.6 +/- 21.9 vs 28.1 +/- 11.5 ng ml-1 h; P < 0.001) and Cmax (8.1 +/- 2.5 vs 3.3 +/- 1.2 ng ml-1; P < 0.001) compared with water. Felodipine tmax (median; 2.8 vs 3.0 h) and t1/2 (7.3 +/- 3.7 vs 6.9 +/- 3.6 h) were not altered. 3. Readministration of Felodipine with grapefruit juice produced mean Felodipine AUC (61.5 +/- 32.2 ng ml-1 h) and Cmax (8.4 +/- 4.8 ng ml-1) which were similar to the initial grapefruit juice treatment 1-3 weeks previously. Felodipine AUC (r = 0.73, P < 0.01) and Cmax (r = 0.69, P < 0.02) correlated between grapefruit juice treatments among individuals. 4. The % increase in Felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in Felodipine Cmax among individuals (r = 0.80, P < 0.01). DehydroFelodipine AUC (74.7 +/- 28.7 vs 48.5 +/- 16.3 ng ml-1 h; P < 0.01) and Cmax (12.1 +/- 2.9 vs 7.9 +/- 2.6 ng ml-1; P < 0.01) were augmented with grapefruit juice compared with water.(ABSTRACT TRUNCATED AT 250 WORDS)
