Fabrication of gastro-floating sustained-release etoricoxib and famotidine tablets: design, optimization, in-vitro, and in-vivo evaluation.

In this study, a new gastro-floating sustained-release tablet (GFT) with a combination of Etoricoxib (ET) and Famotidine (FM) was successfully developed. GFTs were prepared by using a combination of hydrophilic swellable natural/semi-synthetic polymers as a controlled-release layer. Through a 24 full factorial statistical experimental design, the effects of formulation factors on the release of GFTs were conducted. The ideal floating tablet (FT) comprised konjac-gum (150 mg), guar-gum (26.57 mg), xanthan-gum (54.17 mg), and HPMC-K15-M (69.25 mg). The ideal FT exhibited a high swelling index (SI) (297.7%) and rapid FLT (around 50 s) in 0.1 N HCl as well as controlled release of ET (22.43% in 1 h and 77.47% in 8 h) and FM (24.89% in 1 h and 93.82% in 8 h) with the absence of any drug-excipient interactions. The AUC0∼72 (ng h/mL) of ET and FM in the GFTs were approximately double-fold of the market, respectively. The relative bioavailability was (207.48 ± 12.02% and 208.51 ± 13.11%) compared with commercial tablets. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. These findings revealed the successful preparation of the sustained-release floating tablet with improved dual drug delivery.

Development and in vitro/in vivo evaluation of famotidine hydrochloride bioadhesive sustained release suspension.

To develop a new kind of famotidine-resin microcapsule for gastric adhesion sustained release by screening out suitable excipients and designing reasonable prescriptions to improve patient drug activities to achieve the expected therapeutic effect. The famotidine drug resin was prepared using the water bath method with carbomer 934 used as coating material. Microcapsules were prepared using the emulsified solvent coating method and appropriate excipients were used to prepare famotidine sustained release suspension. Pharmacokinetics of the developed microcapsules were studied in the gastrointestinal tract of rats. The self-made sustained-release suspension of famotidine hydrochloride effectively reduced the blood concentration and prolonged the action time. The relative bioavailability of the self-made suspension of the famotidine hydrochloride to the commercially available famotidine hydrochloride was 146.44%, with an average retention time of about 5h longer, which indicated that the new suspension had acceptable adhesion properties. The findings showed that the newly developed famotidine-resin microcapsule increased the bioavailability of the drug with a significant sustained-release property.

Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier.

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 µM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents. SIGNIFICANCE STATEMENT: This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.

Spectroscopic interaction studies of H2 receptor antagonists with levocetirizine.

Patients with allergic rhinitis may also suffer abdominal pain, gastritis or peptic ulcer. In this condition patient may use levocetirizine with famotidine or ranitidine. These drugs have potential to interact with another drug and form complex. The aim of the present study is to evaluate the possible drug drug interaction with each other which may cause increase or decrease of therapeutic effects. For this purpose, validity of Beer Lambert law was checked, lone availability of famotidine (20gm), ranitidine (150gm) and levocetirizine (5mg) were studied in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9 and finally percent availabilities of these drugs were calculated with the help of simultaneous equation. Results showed high percentage of levocetirizine in all pH as 300.32%, 514.41%, 173.38% and 220.68% in presence of famotidine but very low availability of famotidine as 5.36%, 35.38%, 51.87% and 10.89% in presence of levocetirizine. In the case of levocetirizine and ranitidine interaction, zero percent levocetirizine was available at pH 1and 9, 56.28% in pH 4 and 191.1% in pH 7.4. On the other hand, ranitidine was available as 95.36%, 127.93%, 41.47% and 144.3%. These results showed that percentage of all drugs were altered in presence of each other due to drug-drug interaction. This may be due to the charge transfer binding capabilities of the drugs which resulted in significantly changed availability of famotidine, ranitidine as well as levocetirizine.

Utilization of In Vitro, In Vivo and In Silico Tools to Evaluate the pH-Dependent Absorption of a BCS Class II Compound and Identify a pH-Effect Mitigating Strategy.

PURPOSE: To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. METHODS: Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. RESULTS: Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. CONCLUSIONS: The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.

In vitro Spectroscopic studies on drug interaction of cefpodoxime proxetil and H2 receptor blockers.

One of the relatively advance 3rd generation cephalosporins, cefpodoxime proxetil, is being used all-around. Generally, these are used for the cure of infections allied to urinary and respiratory tract. These cephalosporins have showed a remarkable in vitro activity against many strains of bacteria which are resistant to other orally used active medicinal substances. It is the first oral 3rd generation cephalosporin to be used in the cure of skin infections. The practice of H2 receptor antagonists, concerning lots of treatments recommended in patients with different types of ulcers and allergic urticarial condition, is raising hazards of unwanted secondary outcomes and drug interactions. Learning of in-vitro interaction between cefpodoxime poxetil and H2 blockers (Ranitidine, Famotidine and Cimetidine) were examined applying UV/Visible spectrophotometry and Infrared spectrometry. In the existence of H2 receptor blockers, the cefpodoxime proxetil availability was found to be decreased in vitro only under specific conditions. Furthermore, complexes of Cefpodoxime proxetil-H2 receptor antagonists were manufactured approving the interaction of these drugs. Finally, the above mentioned spectrophotometric techniques were employed to examine the complexes formed (Cefpodoxime proxetil-cimetidine, cefpodoxime proxetil-famotidine and cefpodoxime proxetil-ranitidine).

Design of PEG-grafted-PLA nanoparticles as oral permeability enhancer for P-gp substrate drug model Famotidine.

Bioavailability of oral drugs can be limited by an intestinal excretion process mediated by P-glycoprotein (P-gp). Polyethylene glycol (PEG) is a known P-gp inhibitor. Dispersion of Famotidine (a P-gp substrate) within PEGylated nanoparticles (NPs) was used to improve its oral bioavailability. In this work, we evaluated the potential impact of NPs prepared from a grafted copolymer of polylactic acid and PEG on P-gp function by studying in vitro permeability of Famotidine across Caco-2 cells. Copolymers of PEG grafted on polylactic acid (PLA) backbone (PLA-g-PEG) were synthesised with 1 mol% and 5 mol% PEG vs. lactic acid monomer using PEG 750 and 2000 Da. The polymers were used to prepare Famotidine-loaded NPs and tested in vitro on Caco-2 cells. Significant decrease in basolateral-to-apical transport of Famotidine was observed when Famotidine was encapsulated in NPs prepared from PLA-g-PEG5%. NPs prepared from PLA-g-PEG5% are promising to improve oral bioavailability of P-gp substrates.

Evaluation of the Effects of Meal Type and Acid-Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated the effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of cilofexor (100- or 30-mg fixed-dose combination with firsocostat) in healthy participants. Cohorts 1 (n = 20, 100 mg) and 2 (n = 30, 30 mg) followed a 3-period, 2-sequence crossover design and evaluated effects of light-fat and high-fat meals. Cohort 3 (n = 30, 100 mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine. Cohort 4 (n = 18, 100 mg) followed a 3-period, 2-sequence crossover design and evaluated the effects of a 40-mg once-daily regimen of omeprazole administered under fasting conditions or following a light-fat meal. Administration with light-fat or high-fat meals resulted in no change and an ∼35% reduction in cilofexor AUC, respectively, relative to the fasting conditions. Under fasting conditions, famotidine increased cilofexor AUC by 3.2-fold and Cmax by 6.1-fold, while omeprazole increased cilofexor AUC by 3.1-fold and Cmax by 4.8-fold. With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations.

Improved gastric residence time of famotidine by raft-forming drug delivery system using DOE.

OBJECTIVE: This study investigated the raft-forming suspension of famotidine as an anti-reflux formulation to improve the oral bioavailability of narrow absorption window drugs by enhancing gastric residence time (GRT) and preventing gastro-esophageal reflux disease (GERD). METHOD: Various combinations of raft-forming agents, such as Tragacanth gum (TG), guar gum (GG), and xanthan gum (XG), were evaluated alongside sodium alginate (SA) to develop an effective raft. Preformulation studies and preliminary screening were conducted to identify the most suitable raft-forming agent, and GG was chosen due to its mucilaginous properties. The formulation was optimized using a 32 full factorial design, with the quantities of GG and SA as independent factors and apparent viscosity and in-vitro drug release (%) as dependent factors. The in vivo floating behavior study was performed for optimized and stabilized formulation. RESULTS: Among the tested batches, F6 was selected as the optimized formulation. It exhibited desirable characteristics such as adequate raft weight for extended floating in gastric fluid, improved apparent viscosity, and a significant percentage of drug release at 12 h. A mathematical model was applied to the in-vitro data to gain insights into the drug release mechanism of the formulation. The stability of the suspension was assessed under accelerated conditions, and it demonstrated satisfactory stability. The formulation remains floating in the Rabbit stomach for more than 12 h. CONCLUSION: It concludes that the developed formulation has enhanced bioavailability in the combination of GG and SA. The floating layer of the raft prevents acid reflux, and the famotidine is retained for an extended period of time in the gastric region, preventing excess acid secretion. The developed formulations are effective for stomach ulcers and GERD, with the effect of reducing acid secretion by H2 receptor antagonists.

Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development.

Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

Investigation of the rat model for preclinical evaluation of pH-dependent oral absorption in humans.

Many pharmaceutically active compounds are weak electrolytes and are ionizable in the pH range experienced throughout the gastrointestinal tract. Changes in protonation state due to pH changes in the gut can have dramatic effects on solubility, dissolution, and permeation through biological barriers. Preclinical assessment of the pH-dependence of oral absorption is critical for compounds possessing pH-dependent solubility. Here we examine pH-dependent solubility and oral exposure in rat for three model compounds, dasatinib, ketoconazole, and mefenamic acid. Dasatinib and ketoconazole are both weak bases, while mefenamic acid is a carboxylic acid. The effects of gastric pH modulators, pentagastrin and famotidine, were investigated in rat PK studies to assess the applicability of using the rat to evaluate the risk of pH-dependent oral exposure for ionizable compounds. Dasatinib showed similar exposure between control and pentagastrin-pretreated groups, and 4.5-fold lower AUC in famotidine-pretreated rats. Ketoconazole showed a 2-fold increase in AUC in pentagastrin-treated rats relative to control, and 4.5-fold lower AUC in famotidine treated rats, relative to the pentagastrin group. Mefenamic acid showed highly similar exposures among control, pentagastrin-pretreated, and famotidine-pretreated groups. The rat model was shown to be useful for compounds displaying pH-dependent solubility and oral absorption that may be affected by gastric pH modulators.

Merging konjac glucomannan with other copolymeric hydrogels as a cutting-edge liquid raft system for dual delivery of etoricoxib and famotidine.

This study aimed to formulate and evaluate a floating raft system for the co-delivery of etoricoxib (ETO) and famotidine (FAM) using a combination of glucomannan with natural/semi-synthetic polysaccharides. Formulation variables affect gelation lag time (GLT), floating lag time (FLT), and release percentage of drugs after 1-8 h, Stability, and viscosity parameters were evaluated. In vivo X-ray studies, followed by the pharmacokinetic study, were performed on human volunteers. Formulations exhibited pseudoplastic behavior for ease of swallowing. The optimum raft system (ORS) comprised 1% Na alginate, 0.1% Low Methoxyl (LM) pectin, 0.8% Konjac glucomannan (KGL), 1% Precirol, and 1% CaCO3. ORS exhibited rapid GLT and FLT (around 42 and 8 sec respectively) in 0.1 N HCl as well as controlled release of ETO (15% in 1 h and 82% in 8 h) and FAM (29% in 1 h and 85% in 8 h). Formulation stability with the absence of any drug-excipient interactions was observed. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. Compared with marketed products, ORS showed superior relative bioavailability for both drugs. These findings revealed the successful preparation of a promising raft system with improved dual drug delivery.

Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria effect.

Impaired absorption of weakly basic drugs in patients with reduced gastric acidity can lead to loss of efficacy of the therapeutic agent. Hence, a robust formulation which can provide adequate exposure in achlorhydric patients is imperative to achieve the desired efficacy. In this report, formulation development of a weakly basic Merck compound A is described. Compound A shows lower solubility at higher pH and thus is prone to reduced exposure under conditions of achlorhydria, as the compound's solubility increases only in environments of less than pH 2. Several formulations with or without an acidifier were developed and characterized by in vitro dissolution and in gastric pH modified dog model to assess their bioperformance in high gastric pH conditions. To predict the bioperformance of these formulations in humans, a dissolution based absorption model was developed and validated against the observed PPI-interaction data in the clinic and the gastric pH-adjusted dog data. An additional absorption model was developed to allow for incorporation of the dog PK data to provide translation of preclinical to clinical exposure. Based on the in vitro dissolution, in silico absorption modeling and preclinical in vivo data, a citric acid-based formulation (F2) was selected for a human pharmacokinetic study. This study showed that exposures from F2 were not meaningfully different in the presence of proton pump inhibitor (PPI) as compared to non-PPI, thus confirming that the F2 formulation was successful in overcoming the achlorhydria effect. These efforts also highlighted that the complementary use of in vitro/in silico/in vivo (IVISIV) tools may be a helpful strategy in the development of formulations to overcome the achlorhydria effect and achieve adequate exposure in patients with high gastric pH.

A novel gastro-retentive osmotic pump capsule using asymmetric membrane technology: in vitro and in vivo evaluation.

PURPOSE: The purpose of this paper is to develop a novel gastro-retentive osmotic pump capsule using asymmetric membrane technology. METHODS: The physical characteristics of capsule walls and drug delivery behaviors of the system were compared through different coating solutions. The formulation with the glycerin and diethyl phthalate ratio of 5:4 appears to be the best. The thickness of asymmetric membranes was evaluated by withdrawing speed. The relation between the two can be fitted to a linear model. The floating abilities were investigated through filling polyethylene oxide of different molecular weight into the capsules. WSR N-80 (molecular weight 200000) is chosen for the longest floating time. Central composite design-response surface methodology was used to investigate the influence of factors on the responses. The in vivo pharmacokinetics were studied in beagle dogs. RESULTS AND CONCLUSIONS: A second-order polynomial equation was fitted to the data, and the actual response values are in good accordance with the predicted ones. The optimized formulation displays a complete drug delivery, zero-order release rate and 12 h floating time. The in vivo study results clearly indicate the controlled and sustained release of Famotidine from the system, and the relative bioavailability of this preparation is about 1.605 in comparison to that of the marketed preparation.

Evaluation of possible pharmacokinetic interaction between methotrexate and proton pump inhibitors in rats.

BACKGROUND: Methotrexate (MTX), an antifolate agent, is primarily eliminated by the kidney. Organic anion transporter 3 (OAT3) contributes to renal MTX clearance. Several studies have shown an association between co-administration of proton pump inhibitors (PPIs) and delayed elimination of MTX, but the findings are conflicting. In this study, we aimed to evaluate whether the differential inhibitory effects of PPIs on the OAT3-mediated transport of MTX are associated with the risks of delayed MTX elimination. METHODS: We investigated the effects of PPIs on rat (r) OAT3-mediated MTX uptake using HEK293T cells expressing rOAT3. To examine whether PPIs could affect the pharmacokinetics of MTX, changes in plasma concentration-time profiles were assessed when MTX (50 mg/kg, ip) and a range of PPIs (2 mg/kg, iv) were administered to rats. RESULTS: In vitro studies demonstrated that PPIs inhibited rOAT3-mediated uptake of MTX, with estimated IC50 values of 2.1-5.2 µM, and a rank order of esomeprazole ≈ lansoprazole ≈ omeprazole > rabeprazole. When MTX and esomeprazole were co-administered to rats, the plasma concentration of MTX 6 h after administration and the t1/2 were significantly higher than those in the vehicle group. The effect of lansoprazole was not significant, but showed a tendency to prolong plasma MTX levels. Famotidine, a histamine H2-receptor antagonist, showed a weak inhibitory effect on rOAT3-mediated MTX uptake, although it did not affect plasma concentration-time profile of MTX in vivo. CONCLUSION: Esomeprazole increases the t1/2 of MTX in rats, which may be partially attributed to the inhibition of rOAT3.

Pentabromobenzyl-RP versus triazole-HILIC columns for separation of the polar basic analytes famotidine and famotidone: LC method development combined with in silico tools to follow the potential consequences of famotidine gastric instability.

The competence of hydrophilic interaction (HILIC) and reversed phase liquid chromatography (RPLC) modes, employing two new stationary phases: triazole- and pentabromobenzyl-bonded silica (PBr), respectively, was inspected for separation of two polar basic analytes: famotidine (FAM) and its acidic degradant famotidone (FON). Comparison of the chromatographic efficiency, greenness, and economy aspects showed that the RPLC is superior to the HILIC. Hence, the RPLC method was adopted and validated adhering to the FDA guidelines showing excellent linearity for FAM (1.0-20.0 µg/mL) with a detection limit of 0.14 µg/mL. The method was applied to study the behavior of FAM in simulated gastric juice (SGJ), where it exhibited rapid degradation yielding FON. This degradation pathway is a probable major reason for the poor bioavailability of FAM. The kinetic study of the gastric degradation of FAM in SGJ demonstrated pseudo-first order reaction with a rate constant of 8.1 × 10-3 min-1. Moreover, FAM degradation has been proven to be pH-dependent and catalyzed by the gastric juice components. Hence, in situ buffered dosage form is recommended to overcome or decrease this problem. Molecular docking study shows that FON is missing a crucial stabilizing interaction with the key amino acid Asp98 causing a reduced activity at hH2R receptor relative to FAM. Moreover, ADMET properties prediction revealed some differences in the toxicity, pharmacokinetics, metabolism, and solubility profiles of FAM and FON.

Effect of gastric acid-reducing agents on the pharmacokinetics and efficacy of lemborexant.

Lemborexant is a dual orexin receptor antagonist approved for treating insomnia. As the solubility of lemborexant is pH-sensitive, the impact of the gastric acid-reducing agent (ARA), famotidine, on lemborexant pharmacokinetics was evaluated in a Phase 1 study. Additionally, post hoc analysis of data from Phase 3 studies examined the potential effect of concomitant ARAs on patient-reported/subjective sleep onset latency (sSOL) in subjects with insomnia. Coadministration of lemborexant 10 mg with famotidine decreased the maximum observed concentration by 27% and delayed time of maximum observed concentration by 0.5 hours. Famotidine did not affect overall lemborexant exposure based on comparison of area under the concentration curves. Concomitant ARA use in the Phase 3 studies did not impact the effect of lemborexant on sSOL; the change from baseline during the last 7 nights of 1 month of treatment with lemborexant 10 mg was -17.1 minutes with vs -17.9 minutes without ARAs. Collectively, these results indicate that lemborexant can be coadministered with ARAs.

Physiologically-Based Pharmacokinetic Modelling of Creatinine-Drug Interactions in the Chronic Kidney Disease Population.

Elevated serum creatinine (SCr ) caused by the inhibition of renal transporter(s) may be misinterpreted as kidney injury. The interpretation is more complicated in patients with chronic kidney disease (CKD) due to altered disposition of creatinine and renal transporter inhibitors. A clinical study was conducted in 17 patients with CKD (estimated glomerular filtration rate 15-59 mL/min/1.73 m2 ); changes in SCr were monitored during trimethoprim treatment (100-200 mg/day), administered to prevent recurrent urinary infection, relative to the baseline level. Additional SCr -interaction data with trimethoprim, cimetidine, and famotidine in patients with CKD were collated from the literature. Our published physiologically-based creatinine model was extended to predict the effect of the CKD on SCr and creatinine-drug interaction. The creatinine-CKD model incorporated age/sex-related differences in creatinine synthesis, CKD-related glomerular filtration deterioration; change in transporter activity either proportional or disproportional to glomerular filtration rate (GFR) decline were explored. Optimized models successfully recovered baseline SCr from 64 patients with CKD (geometric mean fold-error of 1.1). Combined with pharmacokinetic models of inhibitors, the creatinine model was used to simulate transporter-mediated creatinine-drug interactions. Use of inhibitor unbound plasma concentrations resulted in 66% of simulated SCr interaction data within the prediction limits, with cimetidine interaction significantly underestimated. Assuming that transporter activity deteriorates disproportional to GFR decline resulted in higher predicted sensitivity to transporter inhibition in patients with CKD relative to healthy patients, consistent with sparse clinical data. For the first time, this novel modelling approach enables quantitative prediction of SCr in CKD and delineation of the effect of disease and renal transporter inhibition in this patient population.

Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative Against SARS-CoV2: An In Silico Analysis.

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.

Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rat organic cation transporter 2 (Slc22a2) and rat multidrug and toxin extrusion 1 (Slc47a1) in ischemia/reperfusion-induced acute kidney injury.

In the proximal tubules of rat (r) kidney, the polyspecific organic cation transporters (OCTs), rOCT1 and rOCT2, mediate the baso-lateral uptake of various organic cations, including many drugs, toxins, and endogenous compounds, and the apical type of H(+)/ organic cation antiporter, rat multidrug and toxin extrusion 1 (rMATE1), mediate the efflux of organic cations. Renal clearances of H(2) receptor antagonists, including famotidine, were reported to be decreased in patients with kidney disease. Therefore, acute kidney injury (AKI) could influence renal excretion and disposition of organic cations accompanied by the regulation of organic cation transporters. The aim of this study was to investigate the pharmacokinetic alteration of cationic drugs and the expression of tubular organic cation transporters, rOCT1, rOCT2, and rMATE1, in ischemia/reperfusion (I/R)-induced AKI rats. I/R-induced AKI increased the plasma concentration of i.v. administrated famotidine, a substrate for rOCT1 and rOCT2, or tetraethylammonium (TEA), a substrate for rOCT1, rOCT2, and rMATE1. The areas under the plasma concentration curves for famotidine and TEA were 2- and 6-fold higher in I/R rats than in sham-operated rats, respectively. The accumulation of TEA into renal slices was significantly decreased, suggesting that organic cation transport activity at the basolateral membranes was reduced in I/R rat kidney. The protein expressions of basolateral rOCT2 and luminal rMATE1 were down-regulated in I/R rat kidneys. These data suggest that the urinary secretion of cationic drugs via epithelial organic cation transporters is decreased in AKI.