Bioavailability Of Nifedipine Research Articles

Effect of Gut Microbiota on the Pharmacokinetics of Nifedipine in Spontaneously Hypertensive Rats.

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC0-t (r = -0.881, p = 0.004) and Cmax (r = -0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman's rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = -0.7126, p = 0.0264) and GCDCA (r = -0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with Cmax (r = -0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1.

FORMULATION AND EVALUATION OF POLYMERIC MICROSPHERES USING BOX–BEHNKEN DESIGN

Objectives: The purpose of this research work was to formulate and systemically evaluate in vitro performances of polymeric microspheres of nifedipine. Methods: Nifedipine microspheres containing two polymers, poloxamer 407 and carbopol 934, were prepared by single emulsion cross-linking technique. Glutaraldehyde was selected as the cross-linking agent. A Box–Behnken design was employed to study the effect of independent variables, polymer concentration (X1), stirring speed (X2), and glutaraldehyde concentration (X3) on the dependent variables particle size, drug entrapment efficiency, and flow properties of microspheres. Results: Results of preliminary trials indicate that the polymer concentration, glutaraldehyde concentration, and stirring speed affected various characteristics of microspheres. The formulated Microspheres were discrete, spherical, and free flowing. The optimized batch exhibited with the narrow particle size of 75 μm, good flow properties, and drug entrapment efficiency of 96%. Conclusion: The polymeric microspheres of nifedipine with excellent flowability and good entrapment efficiency were successfully developed. These can be useful in improving patient compliance and bioavailability of nifedipine.

Enhancement of Dissolution Rate and Bioavailability of Nifedipine by Chitosan Based Cocrystallization Technique

The objective of present study was to enhance solubility and dissolution behaviour of nifedipine by using cocrystallization method. A significant increase in solubility and dissolution rate of nifedipine has been demonstrated by solvent change method using chitosan. In this method, chitosan was precipitated on nifedipine crystals using sodium citrate as a salting out agent. An accurately weighed chitosan was dissolved in 1% acetic acid and drug was added in the chitosan solution. This resulting solution was added drop wise into 1% sodium citrate solution with continuous stirring. Sodium citrate precipitate polymer on drug crystals. FTIR, DSC, XRD, SEM, In-vitro dissolution studies, were studied for characterization of prepared cocrystals. Stability studies showed a good stability character of prepared cocrystals. Design Expert® software version 10.0 was used to develop polynomial models which were analysed to delineate the main effects for each CQA (critical quality attributes) through Box-Bhenken design expert. Pharmacokinetic study clearly showed the enhancement of dissolution rate of cocrystals. The above investigation concluded that the significant dose reduction is possible for nifedipine with cocrystal formulation which leads to improve patient compliance.

Nanosuspensions by Solid Lipid Nanoparticles method for the Formulation and In vitro/in vivo, characterization of Nifedipine

Nifedipine is a dihydropyridine calcium channel antagonist initially prescribed for treatment of angina pectoris and hypertension. The drug belongs to BCS Class-2 drug, is poorly water soluble drug, it suffers from a poor aqueous solubility, hence the delays its onset of action. Therefore, the purpose of the research study is to adopt the nanotechnology to formulate nanoparticles that improve the rate of dissolution of drug and to get desired bioavailability of nifedipine. Nanosuspensions were prepared by Solid Lipid Nano Particles method in the presence of selected stabilizers at different concentrations. The nanosuspensions were determined for their particle size of drug, zeta potential of drug, drug content and drug dissolution. The selected formula was freeze dried and illustrated by scanning electron microscopy (SEM), FT-IR, differential scanning calorimetry (DSC), and pharmacokinetic study. The in vitro dissolution confirmed the rate of drug release greater compared to the pure drug. The optimum formula has a typical particle size of 225.56±4.65nm and zeta potential of -17.84±2.17 mV. The bioavailability parameters in the rabbits were enhanced by 2 folds when compared with the marketed tablets (Calcigard®). Solid lipid nanoparticles method was successfully employed to produce stable Nifedipine nanosuspension by using the suitable concentration of stabilizer (PVA, Tween 80, PVP and HPMC). From this study, it is concluded that formulation of Nifedipine nanosuspension may be a competent approach that boost the rate of dissolution and hence oral bioavailability of drug.

A Liposomal Formulation for Improving Solubility and Oral Bioavailability of Nifedipine.

Proliposomes were used to improve the solubility and oral bioavailability of nifedipine. Nifedipine proliposomes were prepared by methanol injection-spray drying method. The response surface method was used to optimize formulation to enhance the encapsulation efficiency (EE%) of nifedipine. The particle size of nifedipine proliposomes after rehydration was 114 nm. Surface morphology of nifedipine proliposomes was observed by a scanning electron microscope (SEM) and interaction of formulation ingredients was assessed by differential scanning calorimetry (DSC). The solubility of nifedipine is improved 24.8 times after forming proliposomes. In vitro release experiment, nifedipine proliposomes had a control release effect, especially in simulated gastric fluid. In vivo, nifedipine proliposomes significantly improved the bioavailability of nifedipine. The area under the concentration-time curve (AUC0–∞) of nifedipine proliposomes was about 10 times than nifedipine after oral administration. The elimination half-life (T1/2β) of nifedipine was increased from 1.6 h to 6.6 h. In conclusion, proliposomes was a promising system to deliver nifedipine through oral route and warranted further investigation.

Role of kaempferol to increase bioavailability and pharmacokinetics of nifedipine in rats.

Herein, the purpose of this study is to evaluate the effects of kaempferol on bioavailability and pharmacokinetics of nifedipine and its metabolite dehydronifedipine in rats. The experimental design is based on with or without kaempferol in the oral and intravenous administration of nifedipine in rats. Moreover, the pharmacokinetic parameters including nifedipine and dehydronifedipine were evaluated in rats.The in vitro studies ofkaempferol were investigated on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity. Kaempferol reduced a 50% inhibitory concentration (IC50) of 8.6 μmol·L-1 on CYP3A4 enzyme activity. Moreover, kaempferol clearly improved the cell internalization of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Depending on increased concentrations of kaempferol, the areas under the plasma concentration-time curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were increased after oral and intravenous administration. Moreover, the absolute bioavailability (AB) and relative bioavailability (RB) of nifedipine in the presence of kaempferol was significantly higher than those of the control group after oral and intravenous administration. Improvement of bioavailability of nifedipine by kaempferol may be mainly because of the inhibition of the P-gp-mediated efflux transporter in the small intestine and CYP3A4-mediated metabolism in the small intestine or liver, or both.

Formulation, Optimization, and In vivo Evaluation of Gastroretentive Drug Delivery System of Nifedipine for the Treatment of Preeclampsia.

The study aimed to develop gastroretentive drug delivery system of nifedipine, its optimization, and in vivo evaluation. Bilayered tablet of nifedipine was prepared using central composite design with 3 factors, 5 responses, and 15 experimental trials. Response surface methodology along with numerical and graphical optimization was used to select the best formulation. Scanning electron microscopy study of optimized tablet at different time interval was carried out which showed formation of porous structure on the tablet surface. In vivo studies for optimized formulation were carried out on 10 healthy human volunteers and obtained pharmacokinetic parameters were compared with the marketed formulation, "Nicardia XL." Optimized formulation containing 3.083mg HPMC K15M, 29.859mg HPMC E15LV, and 3.541mg Carbopol 974P releases the drug in a desired manner and remain buoyant for more than 12h in human stomach. Both the formulations were found to have similar in vitro release profile (f1 4.5089 and f2 55.8274) and also were found to be bioequivalent. Finally, the stability study of the optimized formulation proved the integrity of the optimized formulation. Hence, the data suggest gastroretention as a promising approach to enhance bioavailability of nifedipine.

Combination of Roll Grinding and High-Pressure Homogenization Can Prepare Stable Bicelles for Drug Delivery.

To improve the solubility of the drug nifedipine (NI), NI-encapsulated lipid-based nanoparticles (NI-LNs) have been prepared from neutral hydrogenated soybean phosphatidylcholine and negatively charged dipalmitoylphosphatidylglycerol at a molar ratio of 5/1 using by roll grinding and high-pressure homogenization. The NI-LNs exhibited high entrapment efficiency, long-term stability, and enhanced NI bioavailability. To better understand their structures, cryo transmission electron microscopy and atomic force microscopy were performed in the present study. Imaging from both instruments revealed that the NI-LNs were bicelles. Structures prepared with a different drug (phenytoin) or with phospholipids (dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine) were also bicelles. Long-term storage, freeze-drying, and high-pressure homogenization did not affect the structures; however, different lipid ratios, or the presence of cholesterol, did result in liposomes (5/0) or micelles (0/5) with different physicochemical properties and stabilities. Considering the result of long-term stability, standard NI-LN bicelles (5/1) showed the most long-term stabilities, providing a useful preparation method for stable bicelles for drug delivery.

Effects of Cilostazol on the Pharmacokinetics of Nifedipine After Oral and Intravenous Administration in Rats

The purpose of this study was to investigate the effects of cilostazol on the bioavailability and pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined following oral and intravenous administration of nifedipine (1.5 and 6.0 mg ・ kg-1) in rats. Cilostazol inhibited CYP3A4 enzyme activity at a 50% inhibitory concentration (IC50) of 4.1 μM. The areas under the plasma concentration–time curve (AUC 0-∞) and the peak concentration (C max) of nifedipine were significantly increased, respectively, in the presence of cilostazol compared to that in the control. The total body clearance (CL/F) was significantly decreased by cilostazol. Consequently, the absolute bioavailability (AB) of nifedipine with cilostazol was significantly higher than that in the control. The metabolite to parent AUC ratio (MR) in the presence of cilostazol was significantly decreased compared to that in the control. The AUC 0-∞ of intravenous nifedipine was significantly increased with cilostazol compared to that in the control. The increased bioavailability of nifedipine in rats can be mainly due to the inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver by cilostazol. In addition, the reduction of CL/F of nifedipine by cilostazol may also be a factor.

Fabrication and characterization of nifedipine loaded β-cyclodextrin nanosponges: An in vitro and in vivo evaluation

Cyclodextrin based nanosponges are gaining much consideration due to their aptitude to augment oral solubility of poorly water-soluble medications such as nifedipine. Here in the contemporary research, diphenyl carbonate was employed for crosslinking the cyclodextrin successfully. DLS studies confirmed particle size in the range of 400–500 nm with monodisperse size distribution. TEM measurement established spherical shape and size range of the nanosuspension. SEM photomicrograph confirmed porous structure of placebo nanosponges while drug loaded nanosponge formulation NS3 revealed solid surface. FTIR studies established no drug-polymer interaction. DSC thermograms showed molecular level dispersion of drug in nanosponges. In vitro drug release exhibited a burst release for first fourth hour and delivered drug in sustained manner for subsequent 24 h. When encapsulated within nanosponges, oral bioavailability of nifedipine was enhanced in comparison to control formulation (Cmax for test formulation was 0.2; 0.055 for control). The fabricated nanosponges displayed admirable stability under normal and stress conditions. %Drug entrapment encountered a slight decline (77.33 ± 1.62% to 74.13 ± 1.47%) during storage while %drug release from initial batch was almost identical when compared with stored nanosponges.

Design and Characterization of Buccoadhesive Liquisolid System of an Antihypertensive Drug.

Nifedipine is an antihypertensive BCS class II drug which has poor bioavailability when given orally. The objective of the present study was to increase the bioavailability of nifedipine, by formulation and evaluation of a buccoadhesive liquisolid system using magnesium aluminium silicate (Neusilin) as both carrier and coating material and dissolution media were selected based on the solubility studies. A mixture of carboxymethylcellulose sodium and carbomer was used as mucoadhesive polymers. Buccoadhesive tablets were prepared by direct compression. FTIR studies confirmed no interaction between drug and excipients. XRD studies indicated change/reduction in crystallinity of drug. The powder characteristics were evaluated by different flow parameters to comply with pharmacopoeial specifications. The dissolution studies for liquisolid compacts and tablet formulations were carried out and it was found that nifedipine liquisolid tablets formulated from bioadhesive polymers containing 49% liquisolid system, 17.5% carbomer, and 7.5% carboxymethylcellulose sodium showed the best results in terms of dissolution properties. Prepared formulation batches were evaluated for swelling, bioadhesion strength, ex vivo residence time, and permeability studies. The optimized batch was showing promising features of the system. Formulating nifedipine as a buccoadhesive tablet allows reduction in dose and offers better control over the plasma levels.

Formulation and Evaluation of Self Nanoemulsifying Drug Delivery System of Nifedipine

Oral route is the most preferred route of drug administration due to its easy accessibility, intake, and wide range of choices making it economical. Currently, greater than 60% of marketed drugs are oral products. Over 90% of therapeutic compounds given orally areknown to possess oral bioavailability limitations. Therefore, there is a need to explore various approaches that can be used to improve oral drug bioavailability besides using physical and chemical means. The objective of this study is to prepare a formulation i.e. self microemulsifying drug delivery system (SMEDDS) of nifedipine with the intention to improve the increase dissolution rate (solubility). This will ensure the quick absorption and uniform bioavailability of nifedipine. Selection of oils, surfactants and co-surfactants was done by determining % transparency and on the basis of compatibility studies by FTIR spectra analysis. Different SMEDDS formulation were prepared of different ratio of oil:surfactantmix (1:9,2:8,3:7,4:6,5:5,6:4,7:3,8:2,9:1) and different ratio of surfactants : cosurfactants. Pseudo ternary phase diagram were constructed by water titration method to obtain a particle micro-emulsion region (on the basis of clarity and transparency). The formulation B-I was optimized because of maximum transparency (87.35%) and maximum % drug entrapment (95.32%). The average droplet size and zeta potential was found 86.05 and -0.189. The solubility of nifedipine increase in SMEDDS formulation upto72.17%.From in vitro dissolution study it was proved that SMEDDS formulation releases drug at faster rate, thus the objective of increase solubility and hence the better dissolution rate for uniform bioavailability via SMEDDS formulation of nifedipine was successfully achieved.

Enhanced dissolution and oral bioavailability of nifedipine by spontaneous emulsifying powders: Effect of solid carriers and dietary state

The objective of this study was to prepare spontaneous emulsifying powder (SEP) for improving dissolution and enhancing oral bioavailability of a poorly water-soluble drug, nifedipine (NDP). In order to investigate the effects of solid carrier properties, such as surface area and pore size, and a concurrent food intake on absorption of NDP in rats, different SEP formulations were prepared by adsorbing liquid spontaneous emulsifying formulation (SEF), composing of polyoxyl 35 castor oil, caprylic/capric glyceride and diethylene glycol monoethyl ether at a ratio of 1:1:8, onto various solid carriers (i.e., silica (FS), porous calcium silicate (PCS) and porous silicon dioxide). The solid characterization by scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction revealed the absence of crystalline NDP in the formulations. SEP also demonstrated excellent spontaneous emulsification properties similar to SEF. The droplet size of emulsions formed after dilution was less than 200nm. The solid carriers (particularly PCS) had significant and positive effect in drug dissolution; the mean dissolution time of SEP containing PCS was considerably improved. SEP also provided a good stability after storage in accelerated and long-term conditions for 6months. The bioavailability study resulted in enhanced values of Cmax and AUC for SEP formulations, when tested in both fasted and fed rats. Furthermore, comparing the AUC in fasted and fed rats, NDP powder exhibited a significant food effect. The difference in bioavailability of NDP in fed compared to fasted state can be avoided by using SEP.

Effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats.

The purpose of this study was to investigate the possible effects of pioglitazone on the pharmacokinetics of nifedipine and its main metabolite, dehydronifedipine, in rats. The effects of pioglitazone on P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4 activities were also evaluated. Nifedipine was mainly metabolized by CYP3A4. The pharmacokinetic parameters of nifedipine and dehydronifedipine were determined after oral and intravenous administrations of nifedipine to rats in the presence and absence of pioglitazone (0.3 and 1.0mg/kg). Pioglitazone inhibited the CYP3A4 enzyme activity in a concentration-dependent manner. Inhibitory concentration (IC50) was 12.1μM. In addition, pioglitazone significantly increased the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The areas under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (C max) of nifedipine were significantly increased by 52.1 and 59.1%, respectively, in the presence of pioglitazone (1.0mg/kg) compared with control group. The total body clearance (CL/F) of nifedipine was significantly (1.0mg/kg) decreased by pioglitazone (35.8%). Consequently, the absolute bioavailability (AB) of nifedipine in the presence of pioglitazone (1.0mg/kg) was significantly higher (25.3%) than that of the control. The metabolite-parent AUC ratio (MR) in the presence of pioglitazone (1.0mg/kg) significantly decreased (23.9%) compared to that of the control group. The increased bioavailability of nifedipine in the presence of pioglitazone may be due to an inhibition of the P-gp-mediated efflux transporter in the small intestine and to the inhibition of the metabolism by inhibition of CYP3A4 in the small intestine and/or the liver, and/or to a reduction of CL/F of nifedipine by pioglitazone.

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

BackgroundThis study aimed to investigate the effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats. MethodsWe determined the pharmacokinetic parameters of nifedipine and dehydronifedipine in rats after oral and intravenous administration of nifedipine without and with HMG-CoA reductase inhibitors.We evaluated the effect of HMG-CoA reductase inhibitors on the activity of P-glycoprotein (P-gp) and cytochrome P450 (CYP)3A4. ResultsAtorvastatin, fluvastatin, pravastatin and simvastatin inhibited CYP3A4 activities; inhibitory concentration (IC50) values were 47.0, 5.2, 15.0 and 3.3μM, respectively. Simvastatin and fluvastatin increased the cellular uptake of rhodamine-123.The area under the plasma concentration–time curve (AUC0–∞) and the peak plasma concentration (Cmax) of oral nifedipine were significantly increased by fluvastatin and simvastatin, respectively, compared to control group. The total body clearance (CL/F) of nifedipine after oral administration with fluvastatin and simvastatin were significantly decreased compared to those of control. The metabolite–parent AUC ratio (MR) of nifedipine with fluvastatin and simvastatin were significantly decreased, which suggested that fluvastatin and simvastatin inhibited metabolism of nifedipine, respectively. The AUC0–∞ of intravenouse nifedipine with fluvastatin and simvastatin was significantly higher than that of the control group. ConclusionThe increased bioavailability of nifedipine may be mainly due to inhibition of both P-gp in the small intestine and CYP3A subfamily-mediated metabolism of nifedipine in the small intestine and/or in the liver and to the reduction of the CL/F of nifedipine by fluvastatin and simvastatin.

Da-Chaihu-Tang alters the pharmacokinetics of nifedipine in rats and a treatment regimen to avoid this.

To investigate the influence of co-administrated Da-Chaihu-Tang (DCT; a traditional Chinese formulation) on the pharmacokinetics of nifedipine, as well as the safe optimal dosing interval to avoid the adverse interactions. A single dose of DCT was administered with nifedipine simultaneously, 2 h before, 30 min before or 30 min after nifedipine administration. Pharmacokinetics of nifedipine with or without DCT were compared. The influences of DCT on nifedipine intestinal mucosal and hepatic metabolism were studied by using rat in-vitro everted jejunal sac model and hepatic microsomes. A simultaneous co-administration of DCT significantly increased the area under concentration-time curve from time zero to infinity (AUC0-inf ) of nifedipine. In-vitro mechanism investigations revealed that DCT inhibited both the intestinal and the hepatic metabolism of nifedipine. Further study on the optimal dosing interval for nifedipine and DCT revealed that administration of DCT 30 min before or after nifedipine did not significantly change the AUC of nifedipine. The bioavailability of nifedipine is significantly increased by a simultaneous oral co-administration of DCT. This increase is caused by the inhibitory effect of DCT on both the intestinal mucosal and the hepatic metabolism of nifedipine. The dose interval between DCT and nifedipine needs to be set for over 30 min to avoid such drug-drug interactions.

Polymeric Nanosuspensions for Enhanced Dissolution of Water Insoluble Drugs

The aim of the present research is to formulate and evaluate polymeric nanosuspensions containing three model water insoluble drugs, nifedipine (NIF), carbamazepine (CBZ), and ibuprofen (IBU) with various physicochemical properties. The nanosuspensions were prepared from hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) by a cosolvent technique with polyethylene glycol (PEG‐300) and water as the cosolvents. Physicochemical and morphological characteristics of the nanosuspensions (particle size, polydispersity index, and crystallinity) have been correlated with the drug release behaviour. The effects of polymer, drug ratio on the physical, morphological, and dissolution characteristics of the drugs are reported. Drug release is significantly enhanced from the nanosuspensions; for example, the maximum NIF, IBU, and CBZ concentrations after 8‐hour dissolution are increased approximately 37, 2, and 1.2 times, respectively, in comparison with the pure powdered drugs. Based on this solubilization enhancement performance, the nanosuspensions have potential for increasing the orally dosed bioavailability of NIF, IBU, and CBZ.

Evidence Against the Involvement of Nutritional Habits in the Inter‐ethnic Variability with Regard to Oral Nifedipine Bioavailability

In order to study if nutritional habits are involved in inter-ethnic differences in nifedipine pharmacokinetics, the bioavailability of a single oral dose of 10 mg nifedipine was studied in ten Mexican healthy volunteers maintained on a typical Mexican corn-rich diet and on a Western corn-free diet according to a randomized cross-over design. AUC0–12 was 283 ± 31 and 327 ± 32 ng h mL−1 whereas Cmax was 107 ± 12 and 134 ± 11 ng mL−1 for the corn-rich and corn-free diets, respectively. There were no significant differences between diets in these parameters. AUC and Cmax values observed in Mexicans with both diets were higher than those reported for Caucasian populations. The results confirm the presence of an inter-ethnic variability with regard to nifedipine pharmacokinetics. These differences, however, do not appear to be due to nutritional habits.

Use of hydrophobins in formulation of water insoluble drugs for oral administration

The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs. Bioavailability of two of these drugs, nifedipine and cyclosporine A (CyA), was tested when administered as a SC3-based suspension. SC3 (in a 1:2 (w/w) drug:SC3 ratio) or 100% PEG400 increased the bioavailability of nifedipine to a similar degree (6 ± 2- and 4 ± 3-fold, respectively) compared to nifedipine powder without additives. Moreover, SC3 (in a 7:1 (w/w) drug:hydrophobin ratio) was as effective as a 20-fold diluted Neoral ® formulation by increasing bioavailability of CyA 2.3 ± 0.3-fold compared to CyA in water. Interestingly, using SC3 in the CyA formulation resulted in a slower uptake ( p < 0.001 in T max) of the drug, with a lower peak concentration ( C max 1.8 mg ml −1) at a later time point ( T max 9 ± 2 h) compared to Neoral ® ( C max 2.2 mg ml −1; T max 3.2 ± 0.2). Consequently, SC3 will result in a more constant, longer lasting drug level in the body. Taken together, hydrophobins are attractive candidates to formulate hydrophobic drugs.

Effect of Lactobacillus casei on the Absorption of Nifedipine from Rat Small Intestine

Lactobacillus casei Shirota strain (L. casei) has a modulating effect on the production of cytokines, which often play important roles in drug metabolism, in the inflamed intestinal mucosa. We evaluated the effect of L. casei administered orally in advance for 4 weeks on the absorption of nifedipine from the rat small intestine. The maximum concentration of nifedipine in plasma after administration into the intestinal loop (0.8 mg/kg) was significantly higher in L. casei-treated rats (3.26 microg/mL) than in those untreated rats (2.33 microg/mL) by 40%. Accordingly, the bioavailability of nifedipine was tended to be higher in the former, while the effect of L. casei on the disposition of intravenously administered nifedipine was negligible. We also found that the availability of nifedipine for the passage through the intestinal mucosa was significantly increased in L. casei-treated rats from the single-pass intestinal perfusion experiments. Therefore, it is likely that the exposure to nifedipine after its administration into rat intestine was increased by oral ingestion of L. casei due to an increase in absorption by increased intestinal availability (decreased metabolic extraction) during passage through the intestinal mucosa. This study has suggested that L. casei has some effect on the metabolic activity in the intestinal mucosa, though it seems to be only mild.