Tuning fluorescence of fexofenadine by switching OFF intramolecular photoinduced electron transfer: Application to development of one-step green and high throughput microwell spectrofluorimetric assay for analysis of tablets and plasma.

Fexofenadine (FEX) is a non-sedating antihistamine commonly used for the treatment of allergic conditions such as seasonal rhinitis and chronic idiopathic urticaria. This study describes the tuning "ON" the intrinsic fluorescence of FEX by switching "OFF" its intramolecular photoinduced electron transfer (PET) through the protonation of the piperidinyl nitrogen atom using sulfuric acid. The resulting fluorescence was utilized as a basis for the development of a highly sensitive microwell spectrofluorimetric assay (MW-SFA) for the one-step determination of FEX in pharmaceutical tablets and plasma. The linear range of the assay was 10-500 ng ml-1, and its limit of quantitation was 25.9 ng ml-1. The proposed MW-SFA was successfully applied to analyze FEX in pharmaceutical tablets and plasma samples, demonstrating good accuracy and precision. The greenness of the assay was confirmed using three metric assessment tools. In conclusion, the MW-SFA is a straightforward, single-step analysis that requires no experimental adjustments. It offers high sensitivity, efficient sample processing, and environmental sustainability. This assay is highly recommended for pharmaceutical quality control and clinical lab use, particularly for measuring FEX levels.

Development of fexofenadine self-microemulsifying delivery systems: an efficient way to improve intestinal permeability.

Aim: The present study aimed to prepare and evaluate fexofenadine self-microemulsifying drug-delivery systems (SMEDDS) formulation and to determine and compare its intestinal permeability using in situ single-pass intestinal perfusion (SPIP) technique.Methods: Fexofenadine-loaded SMEDDS were prepared and optimized. Droplet size, polydispersity index, zeta potential, drug release and intestinal permeability were evaluated.Results: Optimized formulation consisted of 15% oil, 80% surfactant and 5% cosolvent. Droplet size and drug loading of optimized formulation was 13.77 nm and 60 mg/g and it has released 90% of its drug content. Intestinal permeability of fexofenadine was threefold enhanced in SMEDDS compared with free fexofenadine.Conclusion: The results of our study revealed that SMEDDS could be a promising tool for oral delivery of fexofenadine with enhanced dissolution rate and intestinal permeability.

[Box: see text].

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.

Designing and Synthesis of Novel Fexofenadine-Derived Hydrazone-Schiff Bases as Potential Urease Inhibitors: In-Vitro, Molecular Docking and DFT Investigations.

Thirteen novel hydrazone-Schiff bases (3-15) of fexofenadine were succesfully synthesized, structurally deduced and finally assessed their capability to inhibit urease enzyme (in vitro). In the series, six compounds 12 (IC50=10.19±0.16 µM), 11 (IC50=15.05±1.11 µM), 10 (IC50=17.01±1.23 µM), 9 (IC50=17.22±0.81 µM), 13 (IC50=19.31±0.18 µM), and 14 (IC50=19.62±0.21 µM) displayed strong inhibitory action better than the standard thiourea (IC50=21.14±0.24 µM), while the remaining compounds displayed significant to less inhibition. LUMO and HOMO showed the transferring of charges from molecules to biological transfer and MEP map showed the chemically reactive zone appropriate for drug action are calculated using DFT. AIM charges, non-bonding orbitals, and ELF are also computed. The urease protein binding analysis benefited from the docking studies.

Cubosomes for Enhancing Intestinal Absorption of Fexofenadine Hydrochloride: In situ and in vivo Investigation.

Purpose: The aim of this work was to probe cubosomes for enhanced intestinal absorption and oral bioavailability of poorly absorbable fexofenadine HCl (FEX-HCl). Materials and Methods: Two cubosomal systems were fabricated utilizing glyceryl mono-oleate, a lyotropic mono lamellar lipid as oil phase and poloxamer407 as stabilizer at weight ratios of 8:2 and 7:3. The morphology of cubosomes was researched using transmission electron microscopy (TEM) and particle size was measured using photon correlation spectroscopy. FEX-HCl release was monitored in vitro. The effect of cubosomal encapsulation on intestinal absorption was assessed using in situ rabbit intestinal perfusion technique. Carrageenan induced rat paw edema model was utilized to monitor in vivo anti-inflammatory effect before and after cubosomal encapsulation. Results: TEM revealed the existence of spherical and polygonal nanostructures arranged in honeycomb organization. Size measurement reflected nanoparticles with reduced size at higher poloxamer concentration. Release studies revealed liberation of FEX-HCl from cubosomes based on Higuchi kinetics model. The intestinal permeability data indicated incomplete absorption of FEX-HCl from simple aqueous solution with P-glycoprotein efflux contributing to this poor intestinal absorption. Incorporation of FEX-HCl in cubosomes enhanced membrane transport parameters. The intestinal absorption did not correlate with drug release suggesting that drug release is not the rate limiting with possible intact cubosomal transport. Cubosomal encapsulation of FEX-HCl significantly enhanced its in vivo anti-inflammatory efficacy compared to the aqueous FEX-HCl dispersion. Conclusion: Cubosomes are promising novel carriers for enhancing intestinal absorption of FEX-HCl. Intact FEX-HCl-cubosomal absorption is possible via trans-lymphatic pathway but this requires further investigations.

Evaluation of UV-C Decontamination of Clinical Tissue Sections for Spatially Resolved Analysis by Mass Spectrometry Imaging (MSI).

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI).

Efficacy of histamine H1 receptor antagonists azelastine and fexofenadine against cutaneous Leishmania major infection.

Current drug therapies for cutaneous leishmaniasis are often difficult to administer and treatment failure is an increasingly common occurrence. The efficacy of anti-leishmanial therapy relies on a combination of anti-parasite activity of drugs and the patient's immune response. Previous studies have reported in vitro antimicrobial activity of histamine 1-receptor antagonists (H1RAs) against different pathogens. We used an ex vivo explant culture of lymph nodes from mice infected with Leishmania major to screen H1RAs compounds. Azelastine (AZ) and Fexofenadine (FX) showed remarkable ex vivo efficacy (EC50 = 0.05 and 1.50 µM respectively) and low in vitro cytotoxicity yielding a high therapeutic index. AZ significantly decreased the expression of H1R and the proinflammatory cytokine IL-1ẞ in the ex vivo system, which were shown to be augmented by histamine addition. The anti-leishmanial efficacy of AZ was enhanced in the presence of T cells from infected mice suggesting an immune-modulatory mechanism of parasite suppression. L. major infected BALB/c mice treated per os with FX or intralesionally with AZ showed a significant reduction of lesion size (FX = 69%; AZ = 52%). Furthermore, there was significant parasite suppression in the lesion (FX = 82%; AZ = 87%) and lymph nodes (FX = 81%; AZ = 36%) with no observable side effects. AZ and FX and potentially other H1RAs are good candidates for assessing efficacy in larger studies as monotherapies or in combination with current anti-leishmanial drugs to treat cutaneous leishmaniasis.

Direct chiral LC-MS/MS analysis of fexofenadine enantiomers in plasma and urine with application in a maternal-fetal pharmacokinetic study.

This study shows the development and validation of two enantioselective LC-MS/MS methods for the determination of fexofenadine in biological matrices including the elution order determination. Plasma (200 µL) or urine (50 µL) aliquots were added to the internal standard solution [(S)-(-)-metoprolol] and extracted in the acid medium with chloroform. Resolution of the (R)-(+)- and (S)-(-)-fexofenadine enantiomers was performed in a Chirobiotic V column. The methods showed linearity at the range of 0.025-100 ng/mL plasma and 0.02-10 µg/mL urine for each fexofenadine enantiomer. These methods were applied to the maternal-fetal pharmacokinetics of fexofenadine enantiomers in plasma and urine of parturient women (n = 8) treated with a single oral 60 mg dose of racemic fexofenadine. Enantiomeric ratio in plasma (AUC0-∞(R)-(+)/(S)-(-)) was close to 1.5, nevertheless in urine was closed to unity. The transplacental transfer was approximately 18% for both fexofenadine enantiomers. The enantioselective methods can also be useful in future clinical studies of chiral discrimination of drug transporters.

Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.

Molecular Mobility of Terfenadine: Investigation by Dielectric Relaxation Spectroscopy and Molecular Dynamics Simulation.

The molecular mobility of an amorphous active pharmaceutical ingredient, terfenadine, was carefully investigated by dielectric relaxation spectroscopy and molecular dynamics simulation for the first time. Comprehensive characterization on a wide frequency (10-2 to 109 Hz) and temperature (300 K) range highlights the fragile nature of this good glass-former (m = 112) and the relatively large nonexponentiality of the main relaxation (ßKWW = 0.53 ± 0.01). In the glassy state, a particularly broad secondary relaxation of intramolecular origin is evidenced. Terfenadine is a flexible molecule, and from molecular dynamics simulation, a clear link is established between the flexibility of the central part of the molecule (carrying, on the one side, the nitrogen group, and on the other side, the OH group) and the distribution of dipole moments, which explains that broadness. Terfenadine is one of the very few cases for which the molecular mobility of the glass obtained by the quench of the melt or by milling can be compared. From the present study, no major difference in terms of molecular mobility is found between these two glasses. However, terfenadine amorphized by milling (for 1-20 h) clearly shows a lower stability than the quenched liquid as we observed its recrystallization upon heating. Interestingly, it is shown that this recrystallization upon heating is not complete and that the 1-2% of the remaining amorphous phase has an original behavior. Indeed, it exhibits an enhanced main mobility induced by an autoconfinement effect created by the surrounding crystalline phase.

An update on the clinical pharmacokinetics of fexofenadine enantiomers.

INTRODUCTION: Fexofenadine is administered as a racemic mixture of (R)- and (S)-enantiomers. The plasma concentrations of (R)-fexofenadine in humans are about 1.5-fold higher than those of the (S)-enantiomer. Such differences in the pharmacokinetics between fexofenadine enantiomers are likely to be dependent on stereoselectivity for affinity to drug-transporters. Areas covered: This review focuses on elucidation of differences in clinical pharmacokinetics between fexofenadine enantiomers. Expert opinion: Differences in pharmacokinetics between fexofenadine enantiomers were caused by organic anion transporting polypeptide (OATP) 2B1, with a minor contribution from P-glycoprotein (P-gp). In vitro studies using OATP2B1 cRNA showed that (R)-fexofenadine uptake into oocytes is greater than (S)-enantiomer uptake. P-gp inducers, carbamazepine, and inhibitors such as itraconazole and verapamil show greater effects on the pharmacokinetics of (S)-fexofenadine. Apple juice and grape fruit juice, OATP2B1 inhibitors, significantly decrease the exposure of both fexofenadine enantiomers, particularly the (S)-enantiomer, but do not change the t1/2. Rifampicin significantly increases plasma concentrations of both enantiomers through inhibition of OATP1B3, whereas enantioselectivity of fexofenadine uptake by OATP1B3-expressing cells has not been observed. Combinations of multiple transporters such as OATP2B1 and P-gp facilitate enantioselective disposition of fexofenadine. Drug-transporters appear to be capable of chiral discrimination for transport of drugs with an asymmetric center.

Enantioseparation of (RS)-fexofenadine and enhanced detection as the diastereomeric amide and anhydride derivatives using liquid chromatography-mass spectrometry.

Enantioselective analysis of (RS)-fexofenadine was carried out by achiral HPLC via a derivatization approach using N-hydroxy-benzotriazolyl-(S)-naproxen ester (synthesized for this purpose) and three chirally pure amines as chiral derivatizing reagents. There occurred formation of amide and anhydride types of diastereomeric derivatives. These were separated and isolated by HPLC (analytical and preparative). The structures and configurations were verified via recording full-scan product ion mass spectra using LC-MS, 1 HNMR spectra, Chem3D Pro 12.0 software and the software Gaussian 09 Rev.A.02 program and hybrid density functional B3LYP with 6-31G basis set supplemented with polarimetry. Experimental conditions for synthesis and separations were optimized and the elution order was established. Analytical separation was performed on a C18 analytical column with different ratios of MeCN-TEAP buffer and MeOH-TEAP buffer (v/v) adjusted to pH 7.5 as mobile phase at a flow rate of 0.7 mL min-1 . Detection was performed via UV absorbance at 225 nm. The method was validated in accordance with International Conference on Harmonization guidelines. The detection limits were 6.25 and 7.87 ng mL-1 for first and second eluting diastereomeric derivatives, respectively.

Differential scanning calorimetry isothermal hold times can impact interpretations of drug-polymer dispersability in amorphous solid dispersions.

Differential scanning calorimetry (DSC) is a commonly employed analytical technique for the analysis and characterization of amorphous solid dispersions. However, steps typical of standard temperature programs can alter the material in situ. Data for two active pharmaceutical ingredients are detailed, wherein isothermal hold times, traditionally employed to remove thermal history and/or residual solvent, were observed to impact the observed dispersability of the compounds in polyvinylpyrrolidone vinyl-acetate copolymer (PVPva). Re-crystallized tolbutamide was observed to re-dissolve in PVPva, while terfenadine was observed to crystallize during the isothermal hold period. Exposing co-solidified drug-polymer mixtures to temperature changes and experimental hold times can potentially confound correct categorization of dispersability, particularly when DSC is used as the lone characterization technique. This work illustrates the importance of using a combination of techniques to improve the certainty of conclusions made with respect to the true, initial physical state of a co-solidified mixture.

Can human allergy drug fexofenadine, an antagonist of histamine (H1) receptor, be used to treat dog and cat? Homology modeling, docking and molecular dynamic Simulation of three H1 receptors in complex with fexofenadine.

Fexofenadine, a potent antagonist to human histamine 1 (H1) receptor, is a non-sedative third generation antihistamine that is widely used to treat various human allergic conditions such as allergic rhinitis, conjunctivitis and atopic dermatitis. Encouragingly, it's been successfully used to treat canine atopic dermatitis, this supports the notion that it might have a great potential for treating other canine allergic conditions and other mammal pets such as dog. Regrettably, while there is a myriad of studies conducted on the interactions of antihistamines with human H1 receptor, the similar studies on non-human pet H1 are considerably scarce. The published studies using the first and second generation antihistamines drugs have shown that the antihistamine response is varied and unpredictable. Thus, to probe its efficacy on pet, the homology models of dog and cat H1 receptors were built based on the crystal structure of human H1 receptor bound to antagonist doxepin (PDB 3RZE) and fexofenadine was subsequently docked to human, dog and cat H1 receptors. The docked complexes are then subjected to 1000ns molecular dynamics (MD) simulations with explicit membrane. Our calculated MM/GBSA binding energies indicated that fexofenadine binds comparably to the three receptors; and our MD data also showed the binding poses, structural and dynamic features among three receptors are very similar. Therefore, our data supported the application of fexofenadine to the H1 related allergic conditions of dog and cat. Nonetheless, subtle systemic differences among human, dog and cat H1 receptors were also identified. Clearly, there is still a space to develop a more selective, potent and safe antihistamine alternatives such as Fexofenadine for dog or cat based on these differences. Our computation approach might provide a fast and economic way to predict if human antihistamine drugs can also be safely and efficaciously administered to animals.

Binding of fexofenadine hydrochloride to bovine serum albumin: structural considerations by spectroscopic techniques and molecular docking.

The binding interaction of peripheral H1 receptor antagonist drug, fexofenadine hydrochloride to bovine serum albumin (BSA) is investigated by fluorescence spectroscopy in combination with UV-absorption spectroscopy under physiological conditions. The Stern-Volmer plots at different temperatures and the steady state fluorescence suggested a static type of interaction between fexofenadine and BSA. Binding constants were determined to provide a measure of the binding affinity between fexofenadine and BSA. It was found that BSA has one binding site for fexofenadine. On the basis of the competitive site marker experiments and thermodynamic results, it was considered that fexofenadine was primarily bound to the site I of BSA mainly by hydrogen bond and van der Waals force. Utilising Förster resonance energy transfer the distance, r between the donor, BSA and acceptor fexofenadine was obtained. Furthermore, the results of circular dichroism and synchronous fluorescence spectrum indicated that the secondary structure of BSA was changed in the presence of fexofenadine. Molecular docking was applied to further define the interaction of fexofenadine with BSA.

Oxidation of cetirizine, fexofenadine and hydrochlorothiazide during ozonation: Kinetics and formation of transformation products.

The efficiency of wastewater ozonation for the abatement of three nitrogen-containing pharmaceuticals, two antihistamine drugs, cetirizine (CTR) and fexofenadine (FXF), and the diuretic drug, hydrochlorothiazide (HCTZ), was investigated. Species-specific second-order rate constants for the reactions of the molecular, protonated (CTR, FXF) or deprotonated (HCTZ) forms of these compounds with ozone were determined. All three compounds are very reactive with ozone (apparent second order rate constants at pH 7: kO3,pH7 = 1.7·10(5) M(-1)s(-1), 8.5·10(4) M(-1)s(-1) and 9.0·10(3) M(-1)s(-1) for CTR, HCTZ and FXF, respectively). Transformation product (TP) structures were elucidated using liquid chromatography coupled with high-resolution tandem mass spectrometry, including isotope-labeled standards. For cetirizine and hydrochlorothiazide 8 TPs each and for fexofenadine 7 TPs were identified. The main TPs of cetirizine and fexofenadine are their respective N-oxides, whereas chlorothiazide forms to almost 100% from hydrochlorothiazide. In the bacteria bioluminescence assay the toxicity was slightly increased only during the ozonation of cetirizine at very high cetirizine concentrations. The main TPs detected in bench-scale experiments were also detected in full-scale ozonation of a municipal wastewater, for >90% elimination of the parent compounds.

The Interesting Case of Acyclovir Delivered Using Chitosan in Humans: Is it a Drug Issue or Formulation Issue?

PURPOSE: Attempts to formulate acyclovir to improve its bioavailability and reduce the frequency of dosing from the present q4h have not materialized. DISCUSSION: It was thought that an approach using permeability enhancer such as chitosan may impart improved absorption profile to acyclovir; however, the recently published pharmacokinetic data suggested otherwise. The lack of promise of chitosan formulation was attributed to the muco-adhesive properties of chitosan to hold off acyclovir and preventing its transport across the gastrointestinal tract. However, the above hypothesis was refuted by another published human pharmacokinetic study of fexofenadine formulated with chitosan formulation - in this work it was unambiguously shown that chitosan helped in enhanced absorption of fexofenadine which is a well-known Pgp substrate. If one examines the pharmacokinetic disposition of acyclovir, it is clear that renal elimination is so rapid necessitating frequent dosing of acyclovir. In summary, the ability of chitosan based formulations to aid in the oral absorption of drugs may be drug dependent as enumerated by data obtained from acyclovir and fexofenadine. While chitosan favourably improved the pharmacokinetics of fexofenadine, acyclovir may not be ideal for chitosan type of formulation. CONCLUSION: The choice of the drug and the formulation type intended to deliver the drug need to be made in a diligent and pragmatic fashion.

The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion.

The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0-24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0-24) by 52% and 61%, respectively, the mean R/S ratios of Ae0-24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.

Effects of Cremophor EL on the absorption of orally administered saquinavir and fexofenadine in healthy subjects.

Modulation of CYP3A and/or P-gp function by several excipients has been reported. However, relatively few studies have investigated their effects in humans. Therefore, the aim of this clinical study was to clarify the effects of Cremophor EL on the inhibition of CYP3A and P-gp in the human small intestine. Eight healthy Japanese subjects received an oral dose of saquinavir (2 mg, substrate of P-gp/CYP3A) or fexofenadine (50 µg, substrate of P-gp) without or with Cremophor EL (720 mg and 1440 mg). Significant increases in Cmax (1.3-fold) and AUC0-24 (1.6-fold) were observed for fexofenadine when administered with 1440 mg of Cremophor EL. In contrast, a significant decrease was observed for saquinavir when administered with 720 mg of Cremophor EL. The equilibrium dialysis experiment was performed to investigate the micellar interaction between Cremophor EL and drugs. The equilibrium dialysis study showed that saquinavir was far extensively entrapped into the micelles. The reduced concentration of free saquinavir by entrapping in micelles was considered to cause the reduction of systemic exposure for saquinavir. In conclusion, this clinical study suggests that Cremophor EL at least inhibits P-gp in the human small intestine.

[Determinants of the stereoselective pharmacokinetics of fexofenadine].

Drug transporters play an important role in the clinical pharmacokinetics of many therapeutic agents. Although it is estimated that about half of all therapeutic agents are chiral, there has been little information on the stereoselective pharmacokinetics related to drug transporters. This review focuses on the drug transporters contributing to the stereoselective pharmacokinetics of fexofenadine enantiomers in humans. Fexofenadine is administered clinically as a racemic mixture, and the plasma concentration of (R)-fexofenadine is about 1.5-fold higher than that of the (S)-enantiomer. Because fexofenadine is poorly metabolized by cytochrome P450s, its pharmacokinetics depends on its drug-transporter activities. First, we examined whether drug-transporter polymorphisms influence fexofenadine enantiomer pharmacokinetics. The findings suggested that a combination of multiple transporters involving organic anion transporting polypeptide (OATP) 2B1, P-glycoprotein (P-gp), and multidrug resistance-associated protein 2 (MRP2) react to stereoselective fexofenadine exposure. Subsequently, we evaluated the roles of P-gp and OATPs in fexofenadine enantiomer pharmacokinetics using these inducer/inhibitors. Coadministration of P-gp inducer/inhibitors significantly altered the pharmacokinetics of fexofenadine enantiomers. In addition, the OATP inhibitors rifampicin and apple juice also affected fexofenadine enantiomer pharmacokinetics. Moreover, in in vitro studies, the uptake of both fexofenadine enantiomers into OATP2B1 cRNA-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. Taken together, these studies indicated that multiple transporters including P-gp, OATPs, and MRP2 play important roles in fexofenadine enantiomer pharmacokinetics. Furthermore, OATP2B1 is a key determinant of the stereoselective pharmacokinetics of fexofenadine, and drug transporters may have chiral discrimination ability.