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Purpose: Croscarmellose sodium, generally used as a superdisintegrant in pharmaceutical formulations, is hydrolyzed to form the gel structure under basic pH conditions. Utilizing this property of croscarmellose sodium, we developed a novel sustained release (SR) system. Methods: Immediate release (IR) and SR tablets containing croscarmellose sodium, alkaline excipients and/or hydroxypropyl methylcellulose (HPMC) were prepared and examined for wet strength and in vitro drug release behavior. In vivo oral drug absorption was evaluated for IR tablets, HPMC tablets and our novel SR tablets in fasted Beagle dogs. Results: To form the gel structure even under the physiological condition, alkaline excipients were added into the formulation containing croscarmellose sodium. Furthermore, HPMC was used to make the gel structure strong enough against mechanical destructive forces. The novel alkalized croscarmellose sodium-HPMC (ACSH) SR tablet, consisting of croscarmellose sodium, alkaline excipients, and HPMC, successfully sustained the release of acetaminophen, ibuprofen, or nicardipine hydrochloride, compared with the IR tablets. The ACSH SR system provided a better release of acetaminophen than the HPMC tablet without croscarmellose sodium in the release study using a small volume of liquid, suggesting that substantial release and subsequent absorption would be expected in the distal intestinal segments after oral dosing. The in vivo oral absorption study revealed that the ACSH SR system successfully suppressed and prolonged the plasma concentrations of acetaminophen. Conclusion: This novel ACSH SR system prepared with croscarmellose sodium, alkaline excipients, and HPMC, would be a promising SR formulation for enabling substantial drug absorption in the distal intestinal segments. [ABSTRACT FROM AUTHOR]

Purpose: The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition. Methods: We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP. Results: ECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (IC50s of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC50 ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold). Conclusions: ECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions. [ABSTRACT FROM AUTHOR]

Purpose: Although curcumin (Cur) has powerful pharmacological effects, its use in medicine has not been established yet. The oral bioavailability (BA) of Cur is limited because of its poor water solubility. The purpose of this study was to confirm whether cationic N,N-dimethyl amino acid esters of Cur could act as prodrugs and improve its water solubility and oral bioavailability. Methods: Two N,N-dimethyl amino acid esters of Cur were synthesized. The hydrolysis profile of the esters was evaluated using rat and human microsomes. A pharmacokinetic study after oral administration of the Cur ester derivatives was performed in rats and compared to the administration of suspended or dissolved Cur formulation. The anti-inflammatory effects of the Cur derivatives were evaluated using macrophage RAW 264.7 stimulated with lipopolysaccharide. Results: Cur ester derivatives showed > 200 mM water solubility. The derivatives were reconverted to the parent compound (Cur) after cleavage of the ester bonds by microsomal esterase, indicating that the compounds could act as Cur prodrugs. The Cur prodrugs enhanced the absolute oral bioavailability of Cur by a 9- and threefold increase of suspended and dissolved Cur administration, respectively, thereby improving intestinal absorption. Cur prodrugs strongly attenuated COX2, iNOS, and ERK phosphorylation. Conclusions: The cationic N,N-dimethyl amino acid ester prodrugs of Cur improved the water solubility of Cur and enhanced oral bioavailability in rats. These Cur prodrugs may be good candidates for developing medicinal options previously unavailable due to the poor water solubility and oral BA of Cur. [ABSTRACT FROM AUTHOR]

Purpose: In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects. Methods: A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation. Results: The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment. Conclusions: Rifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol. [ABSTRACT FROM AUTHOR]

Purpose : Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine. Methods: An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules. Results: The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules. Conclusion: We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide. [ABSTRACT FROM AUTHOR]

Purpose: Despite no broad, direct evidence in humans, there is a potential concern that surfactants alter active or passive drug intestinal permeation to modulate oral drug absorption. The purpose of this study was to investigate the impact of the surfactant polysorbate 80 on active and passive intestinal drug absorption in humans. Methods: The human (n = 12) pharmacokinetics (PK) of three probe substrates of intestinal absorption, valacyclovir, chenodeoxycholic acid (CDCA), and enalaprilat, were assessed. Endogenous bile acid levels were assessed as a secondary measure of transporter and microbiota impact. Results: Polysorbate 80 did not inhibit peptide transporter 1 (PepT1)- or apical sodium bile acid transporter (ASBT)-mediated PK of valacyclovir and CDCA, respectively. Polysorbate 80 did not increase enalaprilat absorption. Modest increases in unconjugated secondary bile acid Cmax ratios suggest a potential alteration of the in vivo intestinal microbiota by polysorbate 80. Conclusions: Polysorbate 80 did not alter intestinal membrane fluidity or cause intestinal membrane disruption. This finding supports regulatory relief of excipient restrictions for Biopharmaceutics Classification System-based biowaivers. [ABSTRACT FROM AUTHOR]

Background: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.Methods: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.Results: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.Conclusion: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence.Graphical Abstract: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway.The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry.Fructose reduced the area under the curve (AUC) and peak concentration (Cmax) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (Peff) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and Cmax of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the Peff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability.Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence. [ABSTRACT FROM AUTHOR]

Purpose: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%.Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.Methods: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%.Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.Results: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%.Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.Conclusion: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1.Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry.Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration–time curve of olmesartan to 76.9%.Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties. Methods: ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared. Results: Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher Cmax (1.4-fold) and AUC0-t (1.3-fold) of ADD than administration of ADD alone, and Cmax and AUC0-t of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability. Conclusion: Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. Methods: Using recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition. Results: The suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine. Conclusions: This study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions. [ABSTRACT FROM AUTHOR]

Purpose: We have previously reported that Capryol 90 improves the intestinal absorption of insulin, a peptide drug, without causing serious damage to the intestinal epithelium. However, the effects of Capryol 90 and its related formulations on the intestinal absorption of other drugs, and their absorption-enhancing mechanisms are still unclear. The aim of this study is to evaluate the effects of Capryol 90 and its related formulations on the intestinal absorption of drugs and elucidate their absorption-enhancing mechanisms. Methods: The intestinal absorption of 5(6)-carboxyfluorescein, fluorescein isothiocyanate-dextrans, and alendronate was evaluated using an in situ closed loop method. Brush border membrane vesicles (BBMVs) were labeled with fluorescent probes, and the fluidity of membrane was evaluated by a fluorescence depolarization method. The expression levels of tight junction (TJ) proteins were measured using a Western blot method and immunofluorescence staining. Results: Among the tested excipients, Capryol 90 significantly improved the small and large intestinal absorption of drugs. In mechanistic studies, Capryol 90 increased the membrane fluidity of lipid bilayers in BBMVs. Additionally, Capryol 90 decreased the expression levels of TJ-associated proteins, namely claudin-4, occludin, and ZO-1. Conclusions: Capryol 90 is an effective absorption enhancer for improving the intestinal absorption of poorly absorbed drugs via both transcellular and paracellular pathways. [ABSTRACT FROM AUTHOR]

Purpose: The poor permeability of new drug candidates across intestinal epithelial membranes complicates their development in oral form. This study investigated the potential of cell-penetrating peptides (CPPs) to improve the intestinal permeation and absorption of low-permeable low-molecular-weight (low-MW) drugs. Methods: The in vitro epithelial permeation of six different drugs (metformin, risedronate, zanamivir, methotrexate [MTX], tacrolimus, and vincristine [VCR]) across Caco-2 cell monolayers was examined in the presence and absence of L- or D-penetratin, and the correlation between permeation enhancement efficiency and the properties of tested drugs was analyzed. In addition, a rat closed ileal loop absorption study was conducted to determine the in vivo effects of penetratin. Results: MTX and VCR efficiently permeated Caco-2 monolayers in the presence of L- and D-penetratin, suggesting that CPPs enhanced the epithelial permeation of drugs with relatively high molecular weight and resultant limited intrinsic permeability. The in vivo rat closed ileal loop absorption study revealed the stimulatory effect of L- and D-penetratin on the intestinal absorption of MTX and VCR. Conclusions: CPPs are useful as oral absorption enhancers for low-permeable drugs. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we investigated organic anion transporting polypeptide 2B1 (OATP2B1)-mediated uptake of fluorescent anions to better identify fluorescent substrates for in vitro OATP2B1 assays. The OATP2B1 is involved in the intestinal absorption and one of the pharmacokinetic determinants of orally administered drugs. Methods: A microplate reader was used to determine the cellular accumulation of the fluorescent compounds into the OATP2B1 or the empty vector-transfected HEK293 cells. Results: Two types of derivatives were found to be OATP2B1 substrates: heavy halogenated derivatives, such as 4′,5′-dibromofluorescein (DBF), and carboxylated derivatives, such as 5-carboxyfluorescein (5-CF). The DBF and 5-CF were transported in a time and concentration-dependent manner. The DBF was transported at a broad pH (pH 6.5–8.0) while 5-CF was transported at an acidic pH (pH 5.5–6.5). The Km values were 0.818 ± 0.067 μM at pH 7.4 for DBF and 8.56 ± 0.41 μM at pH 5.5 for 5-CF. The OATP2B1 inhibitors, including atorvastatin, bromosulfophthalein, glibenclamide, sulfasalazine, talinolol, and estrone 3-sulfate, inhibited the DBF and the 5-CF transport. Contrastively, testosterone, dehydroepiandrosterone sulfate, and progesterone inhibited the DBF transport but stimulated the 5-CF transport. Natural flavonoid aglycones, such as naringenin and baicalein, also exhibited substrate-dependent effects in this manner. Conclusion: We found two fluorescein analogs, DBF and 5-CF as the OATP2B1 substrates that exhibited substrate-dependent interactions. [ABSTRACT FROM AUTHOR]

Purpose: Here, first experiences with a prototype tool for high throughput (passive) permeability profiling, a 96-well plate comprising the Permeapad® membrane, are reported. The permeabilities of a set of drugs were determined and compared to published measures of oral absorption, such as human fraction absorbed (Fa) and in vitro permeability values obtained using other tools. Methods: The tool consists of a 96-well bottom and screen plate with the artificial, phospholipid-based barrier (Permeapad®) mounted between the plates' lower and upper compartments. The permeability of 14 model compounds including high- and low-absorption drugs, cationic, anionic, zwitterionic and neutral molecules, was determined by quantifying the compounds' transport over time, deriving the steady-state flux from the linear part of the cumulative curves and calculating the apparent permeability (Papp). The membrane structure was investigated in a high-resolution digital light microscope. Results: The Permeapad® 96-well plate was found suited to distinguish high and low absorption drugs and yielded a hyperbolic correlation to Fa. The Papp values obtained were congruent with those determined with in-house prepared Permeapad® in the Franz cell set-up. Furthermore, good to excellent correlations were seen with Caco-2 permeability (R2 = 0.70) and PAMPA permeability (R2 = 0.89). Microscopic investigation of the Permeapad® barrier revealed the formation of phospholipid vesicles and myelin figures in aqueous environment. Conclusion: The Permeapad® 96-well plate permeation set-up is a promising new tool for rapid and reproducible passive permeability profiling. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. Methods: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. Results: 250–300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. Conclusion: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane. [ABSTRACT FROM AUTHOR]

Purpose: Different anesthetic regimens are used during single pass intestinal perfusion (SPIP) experiments for the study of intestinal drug absorption in rats. We examined the ketamine/xylazine anesthetic combination to evaluate its influence on drug absorption compared to older regimens. Additionally, we examined whether supplementary analgesia has any effect on drug absorption and the effect of the different anesthetic regimens on induction time and stress response. Methods: Rats were anesthetized using four different anesthetic regimens; ketamine/midazolam, pentobarbital, ketamine/xylazine and ketamine/xylazine/butorphanol. Three model drugs were administered to rat intestines and Peff was calculated. Stress response was evaluated by quantifying blood corticosterone levels and induction time was recorded. Results: We found absorption under pentobarbital to be higher or similar to absorption under ketamine/midazolam. These results partly correlate with past literature data. Ketamine/xylazine was found to give similar or higher Peff compared to pentobarbital and ketamine/midazolam. Addition of butorphanol did not affect absorption and reduced induction time and stress. Conclusions: In studies of intestinal drug absorption, the ketamine/xylazine combination is superior to other anesthetic regimens as it is more convenient and seems to affect absorption to a lesser extent. Addition of butorphanol is highly recommended as it did not affect absorption but led to a more effective and less stress inducing experiment. [ABSTRACT FROM AUTHOR]

Purpose: Mucins are the principal glycoproteins in mucus and have been implicated in the limitation of intestinal drug absorption; however, the contribution of these molecules to intestinal drug absorption remains unclear. In this study, the relationship between the effect of the mucus layer on intestinal drug permeation and mucin distribution in different parts of the rat gastrointestinal tract was evaluated. Methods: The intestinal permeability of various lipophilic drugs in rat small intestine was evaluated using the in vitro sac method. The expression profiles of mucin mRNA and proteins were evaluated by quantitative real-time RT-PCR and western blotting, respectively. Results: The intestinal permeability of griseofulvin and antipyrine was enhanced by dithiothreitol (DTT) treatment in the proximal small intestine, such as duodenum and jejunum, but not in the distal regions. The mRNA expression analysis of rat mucin genes revealed that the intestinal expression of Muc5ac was considerably higher in the duodenum, whereas that of Muc1, Muc2, and Muc3A was gradually increased toward the lower intestine. In addition, Muc5ac protein was detected only in the luminal fluids from the proximal small intestine after DTT treatment. Conclusions: Mucus limits the intestinal permeation of lipophilic drugs in the rat proximal small intestine, in which Muc5ac may be involved. [ABSTRACT FROM AUTHOR]

Purpose To identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs). Methods Caco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer. Results Most undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, ILC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco- 2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion. Conclusions Most LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products. [ABSTRACT FROM AUTHOR]

Purpose: We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. Methods: Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. Results: Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. Conclusion: The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir. [ABSTRACT FROM AUTHOR]

Purpose: This report describes the effect of rhamnolipids (RLs) on the tight junctions (TJ) of the intestinal epithelium using the rat in-situ closed loop model. Methods: We investigated the transport of 5 (6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextrans with average molecular weights of 4.4 and 10 kDa (FD-4 and FD-10) when co-administered with different concentrations of RLs. Lactate dehydrogenase (LDH) leakage assay and histopathological examination of treated intestinal loops were used to assess potential toxicity of RLs. Further, the effect of kaempferol on accelerating the resealing of the tight junctions in vivo was also investigated Results: Data shows that administration of different RLs concentrations (1.0-5.0% v/v) increased CF absorption through rat intestine by 2.84- and 15.82-folds with RLs concentrations of 1.0% and 5.0% v/v, respectively. RLs exhibited size-dependent increase on FD-4 and FD-10 absorption. Dosing RLs at 1.0% v/v didn't cause a significant LDH leakage or histopathological changes to intestinal mucosa compared to higher concentrations, which showed a progressive damaging effect. Using kaempferol, a natural flavonoid that stimulates the assembly of the TJs, proved to enhance the recovery of barrier properties of the intestinal mucosa treated with high concentrations of RLs (2.5% and 5% v/v). Conclusions: These results collectively illustrate the ability of RLs to enhance oral bioavailability of different molecules across the intestinal epithelial membrane in a concentration- and time-dependent fashion. [ABSTRACT FROM AUTHOR]

Purpose: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. Methods: A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). Results: The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate ( K = 44.1 mg/kg, V = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E function describing reversal of hyperalgesia ( EC = 16.7 μg/mL, EC = 3.3 μg/mL). Conclusions: The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin. [ABSTRACT FROM AUTHOR]

Purpose: Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations Methods: Pharmacokinetic parameters were determined following a range of intravenous (5-100 mg/kg) and oral doses (10-200 mg/kg) in rats. Transepithelial transport (50 μM-50 mM) and apical uptake of gabapentin (0.01-50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro. Results: Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine. Conclusions: The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall. [ABSTRACT FROM AUTHOR]

Purpose: Medium chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. Novel oily suspension (OS) formulation disperses a powder containing sodium caprylate and macromolecules such as octreotide or fluorescent dextran (FD). Formulation safety, macromolecule absorption and pharmacokinetic (PK)/pharmacodynamic (PD) were evaluated. Methods: Octreotide/OS toxicity was evaluated in monkeys following 9 months of daily oral enteric-coated capsule administration. The OS permeation effect was also assessed in rats, using FD/OS and octreotide/OS preparations. Octreotide/OS effects on circulating growth hormone (GH) levels were also measured. Results: Safety assessment of octreotide/OS in monkeys after 9 months showed minor drug-related findings, comparable to the injectable octreotide. Octreotide exposure levels were similar across the treatment periods. In rats, OS facilitated FD permeation up to 70 kDa in a reversible, spatial and dose-dependent manner, independent of the intestinal dosing site. Following OS administration, the staining pattern of the tight-junction protein, ZO-1, changed transiently, and a paracellular penetration marker, LC-biotin, permeated between adjacent epithelial cells. Enteral octreotide/OS absorption was dose-dependent and suppressed rat GH levels. Conclusions: Oral octreotide/OS dosing was shown to be safe in monkeys. OS enhances intestinal absorption of active octreotide, likely by transient alteration of the tight junction protein complex. [ABSTRACT FROM AUTHOR]

Purpose: OATP2B1-mediated grapefruit juice (GFJ)-drug interactions are substrate-dependent; for example, GFJ ingestion significantly reduces bioavailability of fexofenadine, but not pravastatin. In the present study, we aimed to establish whether this observation can be explained by the presence of multiple binding sites (MBS) on OATP2B1. Methods: OATP2B1-mediated drug uptake was evaluated using a Xenopus oocyte expression system. Drug concentration was quantified by LC/MS/MS analysis. Results: OATP2B1-mediated uptake of pravastatin and fexofenadine exhibited biphasic saturation kinetics, indicating the presence of MBS on OATP2B1. GFJ strongly inhibited pravastatin uptake mediated by the high-affinity site on OATP2B1, while no significant inhibition of the low-affinity site was observed. In contrast, high-affinity transport of fexofenadine was only modestly inhibited by GFJ, while significant inhibition of the low-affinity site was observed. Contribution analysis indicated that both drugs are transported via the low-affinity site on OATP2B1 at therapeutically relevant concentrations. These findings indicate that only fexofenadine is expected to interact with GFJ on OATP2B1 at therapeutic concentrations, in accordance with the clinical observations. Conclusion: Substrate- and dose-dependent GFJ-drug interactions mediated by OATP2B1 might be explained in terms of the presence of MBS: interaction occurs only when drug and GFJ components share the same binding site on OATP2B1. [ABSTRACT FROM AUTHOR]

Purpose: Superior bioavailability of BCS Class 2 compounds incorporated into SNEDDS was previously reported. This study aims to elucidate the underlying mechanisms accountable for this phenomenon. Methods: SNEDDS of amiodarone (AM) and talinolol were developed. Pharmacokinetic parameters were assessed in vivo. Effect on intestinal permeability, P-gp efflux and toxicity was evaluated in vitro (Caco-2) and ex vivo (Ussing). Solubilization was assessed in vitro (Dynamic Lipolysis Model). Effect on intraenterocyte metabolism was evaluated using CYP3A4 microsomes. Results: Oral administration of AM-SNEDDS and talinolol-SNEDDS resulted in higher and less variable AUC and Cmax. In vitro, higher talinolol-SNEDDS Papp indicated Pgp inhibition. Lipolysis of AM-SNEDDS resulted in higher AM concentration in the fraction available for absorption. Incubation of AM-SNEDDS with CYP3A4 indicated CYP inhibition. SNEDDS didn’t alter mannitol Papp and TEER. SNEDDS effect was transient. Conclusions: Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux. SNEDDS effect is reversible and doesn’t cause intestinal tissue or cell damage. These comprehensive findings can be used for intelligent selection of drugs for which oral bioavailability will improve upon incorporation into SNEDDS, based on recognition of the drug’s absorption barriers and the ability of SNEDDS to overcome them. [ABSTRACT FROM AUTHOR]

In today's pharmaceutical research and development, physiologically-based pharmacokinetic (PBPK) modeling plays an important role in the design, evaluation and interpretation of pharmacokinetic, toxicokinetic and formulation studies. PBPK models incorporate in vitro physicochemical and biochemical data in a physiologically based model framework to simulate in vivo exposure. The comparison of simulated concentrations to those measured in in vivo studies can be used to gain insights into compound behavior and to inform PBPK based human pharmacokinetic predictions. The Göttingen minipig is gaining importance as a large animal model in pharmaceutical research due to its physiological and anatomical similarities to human and is increasingly replacing dog and non-human primate in preclinical studies. However, no PBPK model for minipig has yet been published. This review discusses the information available to establish the physiological database for this species and highlights the gaps in current knowledge. A preliminary PBPK model is created from this database and simulations for two drugs dosed both intravenously and orally are compared to measured plasma concentrations. Results support the validity of the model with simulated plasma concentrations within the range of the observations. In conclusion, the model will need to be refined as additional physiological data become available, but it can already provide useful simulations to assist pharmaceutical research and development in the minipig. [ABSTRACT FROM AUTHOR]

Purpose: CYP3A4 and P-glycoprotein (P-gp) are present in the human intestine and mediate intestinal first-pass metabolism and the efflux of oral drugs, respectively. We aimed to predict whether intestinal CYP3A4/P-gp is saturated in a therapeutic dose range. Methods: Information on the Michaelis-Menten constant (Km), product of the fraction absorbed (Fa) and intestinal availability (Fg) (FaFg) of CYP3A4/P-gp substrates, and clinical AUC data including two or more different dosages for each CYP3A4/P-gp substrate was collected. The relationship between dose-normalized AUC and dose/Km value, termed the linearity index (LIN), was analyzed. Results: Among 38 CYP3A4 and/or P-gp substrates, 16 substrates exhibited nonlinear pharmacokinetics and 22 substrates exhibited linear pharmacokinetics. Substrates with a small LIN tended to exhibit linear pharmacokinetics. The smallest LIN values of a substrate that exhibited nonlinear pharmacokinetics were 2.8 and 0.77 L for CYP3A4 and P-gp substrates, respectively. A decision tree for predicting nonlinear pharmacokinetics of CYP3A4/P-gp substrates based on LIN and FaFg of drugs was proposed. This decision tree correctly predicted linearity or nonlinearity for 24 of 29 drugs. Conclusions: LIN is useful for predicting CYP3A4/P-gp-mediated nonlinearity in intestinal absorption process in humans. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to clarify the impact of organic anion transporting polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. Methods: OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. Results: Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC value of 30.4 μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. Conclusion: Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats. [ABSTRACT FROM AUTHOR]

This study investigated the role of an ABC transporter, Mrp3/ Abcc3 in intestinal folate absorption. Plasma concentrations of folic acid and leucovorin, given orally, were determined in wild-type and Mrp3 −/− mice. Mucosal-to-serosal transport was determined in the everted intestinal sacs. The plasma concentrations of endogenous 5-methyltetrahydrofolic acid, homocysteine and vitamin B12, and mRNA levels of hepatic and intestinal folate metabolizing enzymes were compared between wild-type and Mrp3 −/− mice. C max and area-under plasma concentration–time curve of folic acid were 3.0- and 2.3-fold lower in Mrp3 −/− mice compared with wild-type mice, whereas the total body clearance was unchanged. Absorption of leucovorin was significantly delayed in Mrp3 −/− mice. Mucosal-to-serosal transport of folic acid and leucovorin was significantly decreased in the duodenum of Mrp3 −/− mice, where their PS serosal was decreased to 6.3 and 22% of that in wild-type mice, respectively. PS serosal of 5-methyltetrahydrofolic acid was moderately decreased in Mrp3 −/− mice. There was no obvious abnormality in folate homeostasis in Mrp3 −/− mice. Mrp3 accounts for the serosal efflux of folic acid and leucovorin, while it makes a moderate contribution to the serosal efflux of 5-methyltetrahydrofolic acid in mice. Mrp3 dysfunction does not disrupt folate homeostasis in mouse. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Methods  Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Results  Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3–4.9 fold increase in $${\text{AUC}}_{{\text{0 - }}\infty } $$) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8–20%), in spite of good absorption (72–75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. Conclusions  The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first examples of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis. Methods  HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids. Results  Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R 2 = 0.86); for the partly ionized ketoconazole other intraluminal parameters were also important. Conclusions  Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. Methods  Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP–BL and BL–AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6′-7′-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. Results  Colchicine exhibited 20-fold higher BL–AP than AP–BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP–BL permeability was increased and BL–AP was decreased by GFJ in a concentration-dependent manner (IC50 values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6′-7′-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL–AP secretion (IC50 values of 90, 592 and 11.6 μM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. Conclusion  The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent. [ABSTRACT FROM AUTHOR]

Abstract Purpose  The purpose of this study is to clarify the impact of P-gp and Oatp on intestinal absorption of the β1-adrenoceptor antagonist talinolol. Methods  P-gp-mediated transport was measured in LLC-PK1/MDR1 cells. Oatp-mediated uptake was evaluated with Xenopus oocytes expressing Oatp1a5. Rat intestinal permeability was measured by the in situ closed loop method. In vivo absorption was pharmacokinetically assessed by measuring plasma concentration after oral administration in rats. Results  In LLC-PK1/MDR1 cells, the permeability of talinolol was markedly higher in the secretory direction than in the absorptive one. The uptake of talinolol by Xenopus oocytes expressing Oatp1a5 was significantly increased compared with that by water-injected oocytes. Naringin inhibited talinolol uptake by Oatp1a5 (IC 50 = 12.7 μM). The reported IC 50 value of naringin for P-gp-mediated transport of talinolol is approximately 2,000 μM. Rat intestinal permeability of talinolol was significantly decreased in the presence of 200 μM naringin, but was significantly increased by 2,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Conclusion  The absorption behavior of talinolol can be explained by the involvement of both P-gp and Oatp, based on characterization of talinolol transport by Oatp1a5 and P-gp, and the effects of naringin. [ABSTRACT FROM AUTHOR]

Abstract Purpose  The oral bioavailability of some therapeutic agents is markedly lower in cynomolgus monkeys than in humans. We investigated small-intestinal absorption of the P-glycoprotein (P-gp) substrates etoposide and digoxin in monkeys to clarify the influence of efflux transport on their intestinal permeability. Methods  The pharmacokinetics of etoposide and digoxin was examined in monkeys and rats after oral and intravenous administration. Intestinal permeability and segmental differences in permeability were investigated with an Ussing-type chamber. Results  The bioavailability of etoposide was 12.9 and 13.9% in monkeys and rats, respectively. Total body clearance of etoposide in monkeys was much less than hepatic blood flow, suggesting that the bioavailability would be limited at intestinal absorption. Marked vectorial transport of etoposide in the secretory direction was observed in rats, especially in the lower small intestine, and segmental differences were consistent with the distribution of P-gp expression. Vectorial transport was minimal in monkey small intestine. Our kinetic analysis indicated that P-gp contributes little to the intestinal permeability of etoposide and digoxin in monkeys, and apical uptake is rate-limiting. Conclusion  Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp. [ABSTRACT FROM AUTHOR]

Abstract Purpose  The purpose is to determine absorption mechanism of five bioactive prenylated flavonoids (baohuoside I, icariin, epimedine A, B, and C) present in heat-processed Epimedium koreanum Nakai (Yin Yanghuo). Methods  Transport of five prenylated flavonoids present in heat-processed herbs were studied in the human intestinal Caco-2 model and the perfused rat intestinal model. Results  In the perfused rat intestinal model, prenylated flavonoids with a monoglucosidic bond (e.g., icariin) was rapidly hydrolyzed into corresponding metabolites (e.g., baohuoside I). In the Caco-2 model, apical to basolateral permeability of a monoglycoside baohuoside I (1.46 × 10−6 cm/sec) was more than 2 folds greater than four prenylated flavonoids with 2 or more sugar moieties (−6 cm/sec). The slow apical to basolateral transport of baohuoside I was the result of efflux. This efflux was carrier-mediated and active since its transport was vectorial, concentration- and temperature-dependent with activation energies greater than 15 kcal/mol. Efflux of baohuoside I was significantly suppressed by inhibitors of BCRP and MRP2, whereas efflux of icariin was significantly inhibited only by p-glycoprotein inhibitor verapamil. Because YHH is often heat-processed for better efficacy, we determined and found the optimal condition for increasing contents of more bioavailable flavonoids (i.e., baohuoside I) to be 160–170°C for 5–7 min. Conclusions  Poor bioavailability of prenylated flavonoids results from their poor intrinsic permeation and transporter-mediated efflux. Heat processing parameters may be optimized to preserve the herb’s bioavailable flavonoids, which help retain and improve its efficacy during processing. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To investigate the use of Carbopol® 974P as a stabilizing agent for supersaturated levels of itraconazole (ITZ) in neutral pH aqueous media and the resultant effects on oral absorption of ITZ. Methods  Carbopol® 974P was incorporated into an EUDRAGIT® L 100-55 carrier matrix at concentrations of 20% and 40% based on polymer weight with the aim of prolonging supersaturated ITZ release from the enteric matrix. Amorphous solid dispersions of ITZ in EUDRAGIT® L 100-55 containing either 20% or 40% Carbopol® 974P were produced by hot-melt extrusion (HME). Solid state analysis of these compositions was performed using differential scanning calorimetry and qualitative energy dispersive X-ray spectroscopy. Dissolution analysis was conducted using a pH change method. Oral absorption of ITZ was evaluated in male Sprague–Dawley rats. Results  Solid state analysis demonstrated that the extruded compositions were entirely amorphous and homogenous with respect to drug distribution in the polymer matrix. Dissolution analysis revealed that the addition of Carbopol® 974P to the EUDRAGIT® L 100-55 carrier system functioned to prolong the release of supersaturated levels of ITZ from the EUDRAGIT® L 100-55 matrix following an acidic-to-neutral pH transition. In vivo evaluation of ITZ absorption revealed that the addition of Carbopol® 974P substantially reduced the absorption variability seen with the EUDRAGIT® L 100-55 carrier system. In addition, the 20% Carbopol® 974P formulation exhibited a five-fold improvement in absorption over our initially reported ITZ particulate dispersion compositions that limited supersaturation of ITZ primarily to the stomach. Conclusions  The results of this study strongly suggest that substantial improvements in oral antifungal therapy with ITZ can be achieved via intestinal targeting and polymeric stabilization of supersaturation. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To assess the contribution of organic anion transporting polypeptide 1a5 (Oatp1a5/Oatp3) in the intestinal absorption of an orally active endothelin receptor antagonist, ()-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylene-dioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic acid (compound-A) in rats. Methods  Uptakes of [14C]compound-A by Oatp1a5-expressing Xenopus laevis oocytes and isolated rat enterocytes were evaluated. Results  The uptake of compound-A by Oatp1a5-expressing oocytes was significantly higher than that by water-injected oocytes and Oatp1a5-mediated uptake was saturable with K m value of 116 μM. Compound-A was taken up into isolated enterocytes in time- and concentration-dependent manners and the estimated K m value was 83 μM, which was close to that for the Oatpt1a5-mediated uptake in oocytes. Both uptakes of compound-A by Oatp1a5-expressing oocytes and enterocytes were pH-sensitive with significantly higher uptake at acidic pH than those at neutral pH. Uptakes of compound-A into Oatp1a5-expressing oocytes and enterocytes were significantly decreased in the presence of Oatp1a5 substrates such as bromosulfophthalein and taurocholic acid. Conclusions  These results consistently suggested that Oatp1a5 is contributing to the intestinal absorption of compound-A at least in part, and the transporter-mediated absorption seems to be maximized at the acidic microenvironment of epithelial cells in the small intestine in rats. [ABSTRACT FROM AUTHOR]

AbstractPurpose??This study aimed to characterize the transepithelial transport of miltefosine (HePC), the first orally effective drug against visceral leishmaniasis, across the intestinal barrier to further understand its oral absorption mechanism.Materials and Methods??Caco-2 cell monolayers were used as anin vitromodel of the human intestinal barrier. The roles of active and passive mechanisms in HePC intestinal transport were investigated and the relative contributions of the transcellular and paracellular routes were estimated.Results??HePC transport was observed to be pH-independent, partially temperature-dependent, linear as a function of time and non-saturable as a function of concentration. The magnitude of HePC transport was quite similar to that of the paracellular marker mannitol, and EDTA treatment led to an increase in HePC transport. Furthermore, HePC transport was found to be similar in the apical-to-basolateral and basolateral-to-apical directions, strongly suggesting that HePC exhibits non-polarized transport and that no MDR-mediated efflux was involved.Conclusions??These results demonstrate that HePC crosses the intestinal epithelium by a non-specific passive pathway and provide evidence supporting a concentration-dependent paracellular transport mechanism, although some transcellular diffusion cannot be ruled out. Considering that HePC opens epithelial tight junctions, this study shows that HePC may promote its own permeation across the intestinal barrier. [ABSTRACT FROM AUTHOR]

AbstractPurpose??Recently identified organic solute transporter (Ost) ? and ? are located on the basolateral membrane of enterocytes and may be responsible for the intestinal absorption of many substrates including bile acids. In the present study, the mechanism governing the transcriptional regulation of their expression was investigated.Methods and Results??To clarify the transcriptional regulation of Osts, reporter gene assays were performed using mouse Ost?/? promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor ? (RXR?) or liver X receptor ? (LXR?) and RXR? into Caco-2 cells induced the transcriptional activities of both Ost ? and ? and further increases were observed following treatment with each agonist. Sequence analyses indicated the presence of IR-1 regions in Ost? and Ost? promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXR?. Furthermore, mutations in IR-1 reduced the FXR- and LXR?-dependent transactivation of Ost?/?. Together with the detection of direct binding of FXR/RXR? and LXR?/RXR? to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ost? and Ost?. In addition, the stimulatory effect of FXR/RXR? and LXR?/RXR? on Ost?, but not on Ost?, was further enhanced by HNF-4?.Conclusions??It was concluded that LXR?/RXR? transcriptionally regulate mouse Ost?/? via IR-1 elements shared with FXR/RXR?. Exposure to FXR/LXR? modulators may affect the disposition of Ost?/? substrates. [ABSTRACT FROM AUTHOR]

Purpose: To provide a comprehensive and up-to-date overview focusing on the extent of lymphatic transport of drugs following intestinal absorption and to summarize available data on the impact of molecular weight, lipophilicity, formulation and prandial state. Methods: Literature was searched for in vivo studies quantifying extent of lymphatic transport of drugs after enteral dosing. Pharmacokinetic data were extracted and summarized. Influence of molecular weight, log P, formulation and prandial state was analyzed using relative bioavailability via lymph (FRL) as the parameter for comparison. The methods and animal models used in the studies were also summarized. Results: Pharmacokinetic data on lymphatic transport were available for 103 drugs. Significantly higher FRL [median (IQR)] was observed in advanced lipid based formulations [54.4% (52.0)] and oil solutions [38.9% (60.8)] compared to simple formulations [2.0% (27.1)], p < 0.0001 and p = 0.004, respectively. Advanced lipid based formulations also provided substantial FRL in drugs with log P < 5, which was not observed in simple formulations and oil solutions. No relation was found between FRL and molecular weight. There were 10 distinct methods used for in vivo testing of lymphatic transport after intestinal absorption so far. Conclusion: Advanced lipid based formulations provide superior ability to increase lymphatic absorption in drugs of various molecular weights and in drugs with moderate to low lipophilicity. [ABSTRACT FROM AUTHOR]