PubMed Health⌕ Search

Biomedical subjects

Ramesh Panchagnula

Publications and source records attributed to Ramesh Panchagnula.

At least 19 recordsLinked to original sources
PubMed2006

Nanoemulsions as versatile formulations for paclitaxel delivery: peroral and dermal delivery studies in rats.

Pathogenesis of psoriasis involves the keratinocytes in epidermis as well as the angiogenesis involving deeper skin layers. So, the drug delivery strategy should be customized to localize paclitaxel (PCL) inside both layers. In this investigation, in order to achieve penetration of PCL into deeper skin layers while minimizing the systemic escape, a nanoemulsion (NE) was formulated and evaluated its in vivo pharmacokinetic performance. Further, the same formulation was explored for peroral bioavailability enhancement of PCL. Upon dermal application, the drug was predominantly localized in deeper skin layers, with minimal systemic escape. When orally administered as NE, PCL was rapidly absorbed reaching a steady-state value of 3.5 microg/ml in 30 minutes, and steady-state levels persisted up to 18 hours. This has amounted to an absolute bioavailability of 70.62%. Inhibition of P-glycoprotein efflux by D-alpha-tocopheryl polyethyleneglycol 1,000 succinate and labrasol would have contributed to the enhanced peroral bioavailability of PCL. This investigation provides direct evidence on the localization of large molecular weight, lipophilic drug, PCL, in dermis. Further, the NE formulation has enhanced the peroral bioavailability significantly to more than 70%. The developed NE formulation was safe and effective for both peroral and dermal delivery of PCL.

Administration, Cutaneous↗
PubMed2006

Functional role of P-glycoprotein in limiting peroral drug absorption: optimizing drug delivery.

P-glycoprotein (P-gp) associated multi-drug resistance is one of the major challenges in the chemotherapy of various cancers. On the other hand, it is now widely recognized that P-gp influences drug transport across various biological membranes. To this end, there is an increasing trend to optimize pharmacokinetics and drug delivery right from the initial stages of drug discovery by exploring all the possible mechanisms involved in 'deliverability'. Recent advances in molecular biology techniques and biochemical characterization methodologies have helped in identification of various transporters involved in absorption or secretion of drugs. P-gp, an efflux pump expressed along the gastrointestinal tract, limits the permeability of many drugs and thus affects their peroral absorption and bioavailability. A fundamental insight and thorough understanding of P-gp and its functional role in limiting drug absorption is critical to improve predictability of dynamic absorption models and aid in selection of new candidates for development, and also widen the scope of peroral delivery for 'challenging' molecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Statistical evaluation of physiological variability of rifampicin in fixed dose combinations.

Tuberculosis is one of the microbial diseases having a long history of its occurrence and yet to be eradicated from the world. Due to the development of bacterial resistance, treatment has changed from monotherapy to combotherapy to fixed dose combinations (FDCs). Rifampicin has been found one of the most important anti-tubercular drugs, however variable bioavailability of rifampicin in some FDCs as well as separate formulations has been reported in the literature, and led to the development of WHO model protocol for evaluation of FDCs for bioequivalence trials. In present investigation, role of physiological variability in rifampicin bioequivalence was studied. Influence of subject's body weight, inter/intra-individual variability of elimination rate and impact of outliers on the decision of bioequivalence were investigated. Normalization of pharmacokinetic measures for bioequivalence (AUC and C(max)) were carried out as per body weights and elimination rate constants of subjects, then different statistical tests like two-way ANOVA, hauschke analysis, normal and log-transformed confidence interval were applied to check for the change in bioequivalence decision. It was found that normalization as per body weights did not play a significant role in the outcome of bioequivalence endpoint. Similarly, elimination rate variability and outliers have been found insignificant regarding final outcome of bioequivalence study. Hence, it has been concluded that physiological variability did not play a significant role in bioequivalence of rifampicin in FDCs.

Analysis of Variance↗
PubMed2006

Simultaneous determination of lamivudine and stavudine in antiretroviral fixed dose combinations by first derivative spectrophotometry and high performance liquid chromatography.

Two methods are described for the simultaneous determination of lamivudine (3TC) and stavudine (d4T) in combined pharmaceutical tablets. The first method depends on first derivative UV-spectrophotometry with zero-crossing measurement technique. The first derivative absorbances at 280 and 300 nm were selected for the determination of stavudine and lamivudine, respectively. The second method is based on the separation of both drugs by high performance liquid chromatography using methanol:water (20:80) as the mobile phase at 0.6 ml/min on a reverse phase column with detection at 270 nm. Both the methods showed good linearity, reproducibility and precision. No spectral or chromatographic interferences from the tablet excipients were found. The proposed methods were suitably applied to the assay of commercial formulations. The procedures were rapid, simple and suitable for routine quality control application.

Chromatography, High Pressure Liquid↗
PubMed2006

An ex vivo characterization of Paclitaxel loaded chitosan films after implantation in mice.

The objective of present investigation was the characterization of chitosan films after in vivo implantation. Chitosan films were prepared at three dose loadings of paclitaxel by classical casting method. They were implanted subcutaneously in Swiss mice in the neck region and were removed at 7, 15, 21 and 30 days post implantation for characterization. In vitro release studies on explanted films were done to observe the influence of the time of implantation and loading on paclitaxel release, which were correlated with amount of paclitaxel remaining in films. Residual amount of paclitaxel remaining in explanted films decreased with increase in loading i.e. after 30 days, the % residual content of drug at 25, 20 and 15 mg loadings (per film) were 13, 20 and 45 % of the initial loading. The in vivo release of paclitaxel from films with higher loadings was higher, indicating that paclitaxel, per se, altered biodegradation of chitosan. Light microscopy and SEM studies of films removed from mice provided qualitative information on the loss of integrity and biodegradation of films with time. Further, FTIR and ATR-FTIR spectra revealed the changes in the film matrix that occur after implantation.

Animals↗
PubMed2005

Development and validation of RP-HPLC and ultraviolet spectrophotometric methods of analysis for the quantitative estimation of antiretroviral drugs in pharmaceutical dosage forms.

A high-performance liquid chromatographic and an UV spectrophotometric method were developed and validated for the quantitative determination of three antiretroviral drugs viz. Lamivudine, Stavudine and Nevirapine that constitute one of the first line regimens in antiretroviral therapy. The different analytical performance parameters such as linearity, precision, accuracy, specificity, limit of detection (LOD) and limit of quantification (LOQ) were determined according to International Conference on Harmonization ICH Q2B guidelines. Chromatography was carried out by isocratic technique on a reversed-phase C-18 SYMMETRY column with mobile phase based and optimized depending on the polarity of the molecules. The UV spectrophotometric determinations were performed at 270, 265 and 313 nm for Lamivudine, Stavudine and Nevirapine, respectively. The linearity of the calibration curves for each analyte in the desired concentration range is good (r(2)>0.999) by both the HPLC and UV methods. Both the methods were accurate and precise with recoveries in the range of 97 and 103% for all the three drugs and relative standard deviation (R.S.D.) <5%. Moreover, the accuracy and precision obtained with HPLC correlated well with the UV method which implied that UV spectroscopy can be a cheap, reliable and less time consuming alternative for chromatographic analysis. The proposed methods are highly sensitive, precise and accurate and hence were successfully applied for the reliable quantification of API content in the commercial formulations of Lamivudine, Stavudine and Nevirapine.

Anti-HIV Agents↗
PubMed2005

In situ and in vivo efficacy of peroral absorption enhancers in rats and correlation to in vitro mechanistic studies.

The present investigation attempts to increase intestinal permeability and hence absorption of biopharmaceutic classification system (BCS) Class III (cefotaxime sodium (CX)) and Class IV (cyclosporin A (CSA)) drugs by employing certain absorption enhancers. Drugs were co-perfused with sodium caprate (SC, 0.25% w/v), piperine (P, 0.004% w/v) and sodium deoxycholate (SD, 1.0% w/v) separately in rat in situ single pass intestinal perfusion model. These additives increased intestinal permeability (P(app)) and absorption rate constant (K(a)) up to two and fourfold, respectively. SC exhibited substantial absorption enhancement of both CX and CSA, while SD and P enhanced absorption of CX and CSA, respectively. Co-administration of SC significantly enhanced peroral bioavailability of CX (from 29.4 +/- 1.7 to 69.6 +/- 3.2) and CSA (from 18.4 +/- 15.6 to 49.6 +/- 25.1) in rats, while P increased bioavailability of CSA (from 18.4 +/- 15.6 to 33.1 +/- 17.7). Transmission electron microscopy of intestinal mucosa revealed that SC and SD act on lipid and protein domains of absorptive membrane. P showed no effect on intestinal P(app) and oral bioavailability of CX but has a profound effect on CSA, a known P-glycoprotein (P-gp) substrate. These results indicated that P enhances intestinal absorption of CSA by modulating P-gp mediated efflux transport. Release of lactate dehydrogenase in situ from intestinal mucosa in the presence of absorption enhancer was taken as index of its local toxicity. All the absorption enhancers showed significantly less release of LDH compared to positive control, sodium dodecyl sulfate (60% w/v). Overall, the data indicate that the features of these commonly used food ingredients or endogenous bile salts can effectively improve bioavailability of various BCS Class III and Class IV drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers.

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.

Animals↗
PubMed2005

Relationship between lipophilicity of BCS class III and IV drugs and the functional activity of peroral absorption enhancers.

Absorption enhancers (AEs) have been shown to be specific in permeation enhancement capabilities because of which they increase absorption of some drug molecules more than others. Present study was designed to investigate the relationship between lipophilicity of drug molecules and the absorption enhancement potential of AEs. Four drug molecules of different lipophilicity were selected as model compounds, namely, cefotaxime sodium, ceftazidime pentahydrate, lovastatin and cyclosporin A. Their apparent permeability coefficients in the absence and presence of three classes of AEs (fatty acids, cyclodextrins, and bile salts) were determined using in vitro everted rat intestinal sac absorption model. Significant relationship was observed between log P of drug and absorption enhancement ratios by AEs. This relationship was found to be functionally directly or indirectly proportional depending upon nature of AE and explain the mechanism of permeation enhancement.

Animals↗
PubMed2005

Feasibility studies of dermal delivery of paclitaxel with binary combinations of ethanol and isopropyl myristate: role of solubility, partitioning and lipid bilayer perturbation.

In the current investigation, paclitaxel (PCL) delivery into the different layers of skin, vehicle optimization and relationship between vehicle composition and the relative contribution of solubility, partition and diffusion towards drug transport has been outlined. Saturation solubility of PCL was determined in ethanol (EtOH), isopropyl myristate (IPM) and their binary combinations, and partition studies performed to study the probability of skin depot formation. Epidermal and dermal partitioning was carried from PCL saturated vehicles. Skin permeation of PCL was studied using the rat skin. FT-IR has been utilized to study the skin barrier perturbation, and the localization of PCL and isopropyl myristate (IPM) in epidermis. High K(app) value in mineral oil/buffer indicated the tendency of PCL to form a reservoir in skin, and an inverse relationship between PCL solubility in different solvent systems and partitioning into epidermis was found. Maximum K(epidermis) for PCL was observed with IPM, while PCL in EtOH/IPM (1:1) showed high partitioning into dermis. Maximum flux of PCL was observed with EtOH/IPM (1:1). For lipophilic drug like PCL modulation of vehicle seems to be effective approach to increase the permeability across the skin. With a binary combination of EtOH/IPM (1:1) higher concentration of PCL can be delivered to deeper layer of skin whereas with IPM higher concentration of PCL could be localized in the epidermis. While engineering the delivery vehicle selection of solvents should be such that one of them is miscible in both hydrophilic and lipophilic phase like ethanol and another should be lipophilic in nature (IPM in this case) so that an optimum balance between 'push-pull' and 'blending' effect can be achieved.

Administration, Cutaneous↗
PubMed2005

Transdermal delivery of naloxone: skin permeation, pharmacokinetic, irritancy and stability studies.

The current investigation aims to evaluate ex vivo, in vivo performance, stability and irritancy potential of a transdermal formulation of naloxone (NLX) developed at our laboratory at different concentrations (10, 20 and 30mg/g of gel) in a transdermal reservoir patch. Ex vivo permeation studies were performed by employing porcine and rat skins. In vivo performance was assessed in Sprague-Dawley rats by single and multiple application of the patch. Further stability of the formulation was established for 3 months at accelerated stability conditions as per ICH guidelines. Amongst the barriers used the rat skin was found to be more permeable than the porcine epidermis and the flux across each barrier increased with increasing thermodynamic activity of drug in the gel. Based on ex vivo data, the surface area (SA) of the patch was predicted to be 39.6 cm(2) in order to achieve therapeutic blood levels. Upon single dose administration, the steady-state levels were maintained from 4-48 h, which proves the clear advantage of transdermal delivery system over the current mode of administration, i.e., intravenous (i.v.) bolus which is effective upto a maximum of 1.5h. Upon multiple dose administration, the sustained steady state for 12h, even after patch removal proves the formation of drug depot in the skin. The formulations were found to be stable with respect to NLX assay and penetration enhancer efficacy upto 3 months under accelerated stability conditions. The alteration of penetration barrier function, as evidenced by increased trans epidermal water loss (TEWL) was not accompanied by any significant amount of skin irritation measured using laser doppler velocimetry (LDV). The developed transdermal delivery system of NLX is efficacious, stable and safe upon single and multiple dose applications each lasting for 48 h.

Administration, Cutaneous↗
PubMed2005

pH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs 1. Simultaneous determination of quinidine and permeability markers in rat in situ perfusion samples.

A simple, specific and sensitive reversed-phase high performance liquid chromatographic (RP-HPLC) method with UV absorbance detection was developed and validated for simultaneous determination of quinidine, verapamil and passive permeability markers, in samples obtained from rat intestinal in situ single-pass perfusion studies. Chromatography was carried out on C18 column with mobile phase comprising of acetate buffer (pH 5.0) and methanol in the ratio of 40:60 (v/v) pumped at a flow rate of 0.6 ml/min and UV detection was employed at 230 and 275 nm. The average retention times for hydrochlorthiazide, frusemide, quinidine, propranolol, and verapamil were 4.9, 5.8, 6.9, 8.9 and 11.3 min, respectively. The calibration curves were linear (R(2)>0.9995) in the selected range for each analyte. The method is specific and sensitive with limit of quantification as 25 ng/ml for quinidine and verapamil. The intra- and inter-day accuracy and precision were found to be good for all the five analytes. The method was found to be reliable in permeability determination and to estimate pH-dependent P-glycoprotein (P-gp)-mediated efflux transport of quinidine. Weak bases quinidine, propranolol and verapamil showed pH-dependent permeability, where quinidine permeability increased by 3.6-fold when the luminal pH was changed from pH 4.5-7.4. Inhibition of P-gp by verapamil (200 microM) indicated that about 68% and only 35% of passive transport of quinidine was attenuated by P-gp-mediated efflux at pH 4.5 and 7.4, respectively. In conclusion, low passive transport rates of weakly basic P-gp substrates at lower pH, may lead to more accessibility of these molecules to P-gp within enterocytes thus resulting in pH-dependent functional activity of P-gp as protic drugs moves along the gastrointestinal tract.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Effect of L-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine.

The aim of this investigation was to study the effect of 1,8-cineole and L-menthol on phase behavior and molecular organization of Stratum corneum (SC) lipids and permeation of zidovudine (AZT) across human cadaver skin (HCS). Permeation studies were conducted across HCS using Franz diffusion cells at 37 degrees C. Differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were employed to understand the effect of terpenes on phase behavior and molecular organization of a model SC lipid system consisting of an equimolar mixture of ceramide, palmitic acid and cholesterol. Both 1,8-cineole and L-menthol applied at 5% w/v in 66.6% ethanol as a vehicle significantly enhanced the pseudosteady state flux of AZT across HCS. The vehicle reduced the number of endothermic transitions observed in the DSC thermogram of a hydrated model SC lipid system from three to two with a lowered midtransition temperature (Tm), while the inclusion of terpenes resulted in a single but very broad endothermic transition for the model SC lipid system. Correspondingly, ATR-FTIR studies revealed that both 1,8-cineole and L-menthol increased CH2 stretching frequencies on either side of lipid transition in addition to lowering the Tm of model SC lipid system by approximately 2-8 degrees C. The alterations observed in the amide-I frequencies of model SC lipid system after the inclusion of terpenes suggest that they disrupt the interlamellar hydrogen-bonding network at the polar head group region. Further, terpenes also increased the hydration levels of the lipid system probably by forming new aqueous channels. These results indicate that terpenes enhance transdermal permeation of AZT and other drugs by transforming SC lipids from a highly ordered orthorhombic perpendicular subcellular packing to a less ordered hexagonal subcell packing.

Animals↗
PubMed2005

Transdermal delivery of imipramine hydrochloride: development and evaluation (in vitro and in vivo) of reservoir gel formulation.

The in vitro permeation studies of imipramine hydrochloride (IMH) reported earlier from our laboratory showed that a combination of menthol (2.5% w/v) and oleic acid (2.5% w/v) worked well in terms of safety and efficacy. The main objective of this study was to evaluate the in vivo performance of this combination; in order to do that, penetration enhancers were incorporated in a hydro-alcoholic gel of hydroxypropylmethyl cellulose along with IMH and used as the drug matrix in a reservoir transdermal patch. A stability study of IMH gel was performed at 40 degrees C/75% RH for 2 months. The results of this study indicate that gels of IMH stored at 40 degrees C/75% RH turned yellow brown in 2 months and the small change in viscosity of gel at 40 degrees C/75% RH had an insignificant effect on the release rate of IMH from the gel (p>0.05). The in vivo performance of the gel was tested in rats using a reservoir transdermal patch, which consisted of a backing membrane, drug matrix and retaining membrane with an area of 12.5 cm2. Plasma concentrations of 3 microg/ml of IMH were achieved and in a histopathological study 24 h occlusion was found to be safe.

Administration, Cutaneous↗
PubMed2005

Implication of biopharmaceutics and pharmacokinetics of rifampicin in variable bioavailability from solid oral dosage forms.

Rifampicin is one of the oldest and most effective chemotherapeutic agents available for the treatment of tuberculosis but exhibits variable bioavailability from separate and fixed dose combination formulations, which has been identified as a major bottleneck in the effective treatment of tuberculosis. In this investigation, physico-chemical characterization, single dose pharmacokinetic studies and the permeability of rifampicin under physiological conditions in the rat were studied to trace the possible reasons for its variable absorption. Rifampicin exhibits very high solubility in acidic and basic pH, corresponding to the pH of the stomach and distal intestine, respectively, whereas it is moderately soluble at the jejunal pH. From single-dose pharmacokinetic studies and permeability characterization, rifampicin is a highly permeable molecule and thus according to BCS, it is a borderline class II drug. This investigation has ruled out the possibility of intrinsic solubility, effective permeability, drug decomposition, presystemic metabolism and interaction with other antituberculosis drugs as direct factors responsible for the variable bioavailability of rifampicin. However, it was found that the rate of dissolution in association with pH and the concentration-dependent absorption of rifampicin affects the in vivo performance of the dosage forms. In addition, this is the first report of methodology for correcting inlet concentration for permeability calculations of a chemically unstable molecule.

Animals↗
PubMed2005

Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability.

The purpose of this study is to determine the functional role of P-glycoprotein (P-gp) in intestinal absorption of drugs and to quantitatively predict the in vivo absorption enhancement on P-gp inhibition. In situ single-pass rat ileum permeability and aqueous solubility were measured for a set of 16 compounds. Permeability studies were also carried out in the presence of P-gp inhibitor to estimate the permeability enhancement on P-gp inhibition. A significant correlation was obtained between rat ileum permeability and the literature human intestinal absorption (HIA), F(a,human) (r = 0.891; p < 0.01). Compounds with permeability >0.2 x 10(-4) cm/s are completely absorbed; however, few practically insoluble compounds were overestimated with this relationship. Inhibition of P-gp increased the permeability (p < 0.05) of three moderately and three highly permeable compounds. Efflux inhibition ratio (EIR), the ratio of permeability due to P-gp-mediated efflux activity and passive permeability only, for these compounds was in the order of digoxin > paclitaxel > fexofenadine > quinidine > verapamil > cyclosporine. Integration of EIR with permeability versus F(a,human) predicted that modulation of P-gp has no significant effect on the absorption of highly permeable compounds (quinidine, verapamil, and cyclosporine A), while for moderately permeable compounds (digoxin, paclitaxel, and fexofenadine), P-gp profoundly influences the intestinal permeability. The in situ permeability in rat ileum may be used to predict the in vivo P-gp function and its quantitative contribution to intestinal drug absorption. Integration of the functional activity of P-gp with the characteristics of BCS may explain drug interactions and explore the possible pharmacokinetic advantage on P-gp inhibition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

pH-dependent functional activity of P-glycoprotein in limiting intestinal absorption of protic drugs: kinetic analysis of quinidine efflux in situ.

The purpose of this investigation is to evaluate the quantitative contribution of pH-dependent passive permeability on the functional activity of P-glycoprotein (P-gp) in limiting intestinal absorption of weakly basic drugs, in order to include this effect in prediction models. pH-dependent octanol/buffer partition coefficient, artificial membrane permeability and in situ rat intestinal permeability of quinidine were determined in the physiological pH range of gastrointestinal tract. In situ permeability, as a function of luminal pH, was also determined in the presence of P-gp inhibitor, verapamil (500 microM). Octanol/buffer partition coefficient, transport across artificial membrane, and rat in situ permeability showed high pH-dependency. Absorption quotient (AQ), calculated from in situ permeability to express the functional activity of P-gp, declined with increase in luminal pH or increase in luminal quinidine concentration because of the increased passive permeability or saturation of P-gp. AQ was 0.57 +/- 0.02 and 0.41 +/- 0.05, while passive permeability was 0.32 +/- 0.01 x 10(-4) cm/sec and 0.43 +/- 0.02 x 10(-4) cm/sec, in jejunum and ileum, respectively, at pH 7.4. Further, apparent Michaelis-Menten constants (K(M), J(P-gp,max)) for the quinidine efflux in jejunum indicated that efflux activity was more at luminal pH 4.5 over pH 7.4. K(M) values for jejunum quinidine efflux at pH 4.5 and pH 7.4 were determined to be 77.63 +/- 10.90 and 22.86 +/- 5.22 microM, with J(P-gp,max) values of 1.47 +/- 0.08 and 0.62 +/- 0.04 nM/cm2/sec, respectively. AQ vs passive permeability showed significant relationship indicating dependency of P-gp-mediated efflux on pH-dependent passive permeability, which is dictated by ionization status for a protic or ampholytic drug. In conclusion, an orally administered drug is absorbed from various segments of intestine, which inherit difference in luminal pH, transcellular permeability and P-gp expression. In situ data suggests that pH-dependency and regional variability in passive permeability of protic substrates significantly influence their P-gp-mediated efflux and may have implications on predictions of the in vivo drug absorption.

ATP Binding Cassette Transporter, Subfamily B, Mem↗