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Purpose: The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations., Methods: Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin., Results: The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K(p,uu)., Conclusions: Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.

Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development. [ABSTRACT FROM AUTHOR]

The objective of the Biopharmaceutics Classification System is to allow prediction of in vivo pharmacokinetic performance of drug products from in vitro measurements; therefore, it is important to determine the solubility and permeability of drug substances. Furosemide (FSM) is a loop diuretic commonly used in the treatment of edematous states associated chronic renal failure, hypertension, congestive heart failure and cirrhosis of the liver. The aim of this study was to develop and validate an HPLC method for quantification of FSM in the samples obtained from the in vitro solubility studies performed at five different pH values (pH 1.0, 2.9, 3.9, 4.9 and 7.5). Chromatographic separation of FSM was achieved on a reverse phase column (Waters Spherisorb ODS2 C18 250x4.6 mm 5 μm) with a mobile phase consisted of 0.01M KH2PO4 (pH 5.5) and methanol (70:30 v/v). Analyses were run at a flow rate 1 mL/min and UV detection was performed at 235 nm. Under these conditions, the retention time of FSM was about 7.0 min. The method was linear in the concentration range of 0.5 to 50 μg/mL, and limit of quantification was 320 ng/mL. Developed and validated HPLC method was proved to be simple, reliable and also suitable as a single method for studying the solubility of FSM as a function of pH. Finally, based on our results, solubility of FSM was dependent on pH. Its solubility was low between pH 1.0 and 4.9, and was high at pH 7.5. [ABSTRACT FROM AUTHOR]

• Atenolol and metoprolol are the preferred drugs in the treatment of hypertension and heart failure. • Importance of assessing intestinal absorption and permeability of orally administered drugs by in-situ perfusion studies. • Use of HPLC as an analytical method in quantification and drug quality control. • Development of an HPLC method that simultaneously detects atenolol, metoprolol, and phenol red (zero permeability marker). Single-pass intestinal perfusion (SPIP) method is a widely used experimental model to determine the intestinal permeability of drugs. These studies are performed in the presence of a reference standard (metoprolol, MT) and a zero permeability marker (phenol red, PR). Therefore, it is important to develop a validated method for simultaneous determination of the investigated compound along with MT and PR. The aim of this study was to develop a reversed phase high-performance liquid chromatography (RP-HPLC) method with UV-detection for the simultaneous determination of atenolol (ATN), MT, and PR in the perfusion medium used in SPIP experiments. Separation of compounds were performed using an InertSustain C18 (250 × 4.6 mm, 5 µm) HPLC column at 35 °C. The mobile phase was a mixture of acetonitrile and phosphate buffer (pH 7.0, 12.5 mM) in gradient elution, and was delivered at a flow rate of 1 mL/min. The acetonitrile ratio of the mobile phase increased linearly from 10 to 35 % over 15 min. The injection volume was 20 µL, and ATN, MT and PR were detected at 224 nm. The retention times under optimum HPLC conditions were 5.028 min, 12.401 min, and 13.507 min for ATN, MT and PR, respectively. The developed RP-HPLC method was validated for selectivity, specificity, calibration curve and range, accuracy and precision, carry-over effect, stability, reinjection reproducibility, recovery and robustness. The method was linear for ATN (0.76–50 μg/mL), MT (1.14–50 μg/mL), and PR (0.47–20 μg/mL) with determination coefficients of 0.9999, 0.9994 and 0.9998, respectively. The results obtained for all validation parameters of the developed RP-HPLC method met the required limits of the ICH M10 Guideline. [ABSTRACT FROM AUTHOR]

Clinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach. Dissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV–vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f 2) and difference (f 1) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R2 adj). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes. The dissolution profiles were not similar at pH 4.5 (f 2 =45.43, f 1 =18.97) and pH 6.8 (f 2 =31.47, f 1 =32.94). CT best fitted with Higuchi (pH 1.2: R2 adj =0.9990), Weibull (pH 4.5: R2 adj =0.9884), and Korsmeyer-Peppas (pH 6.8: R2 adj =0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R2 adj =0.9986), logistic (pH 4.5: R2 adj =0.9839) and first-order (pH 6.8: R2 adj =0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p =0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets. Crushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube. [Display omitted] [ABSTRACT FROM AUTHOR]

This study investigates the hepatic disposition of diclofenac as a function of route of input: portal vein (PV) versus hepatic artery (HA) in the presence of its binding protein, albumin. The in situ dual perfused rat liver was performed using Krebs bicarbonate buffer containing human serum albumin (HSA, 0.25%-1%) at constant PV (12 mL/min) and HA (3 mL/min) flow rates. Bolus doses of [14C]-diclofenac and 125I-labeled HSA were injected randomly into the HA or PV and then, after an appropriate interval, into the alternate vessel. Regardless of route of input and perfusion medium protein concentration, the hepatic outflow profile of diclofenac displayed a characteristic sharp peak followed by a slower eluting tail, indicating that its radial distribution is not instantaneous. Based on the estimated effective permeability-surface area product/blood flow ratio, hepatic uptake of diclofenac is governed by both perfusion and permeability. Fractional effluent recovery ( F) increased as unbound diclofenac fraction in the perfusate decreased. Although no significant difference in hepatic clearance of diclofenac as a function of route of delivery at 0.5% and 1% HSA, it was demonstrable at 0.25% HSA ( p < 0.001), when the extraction ratio is higher. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3220-3227, 2013 [ABSTRACT FROM AUTHOR]

Cardioselective β-adrenergic blocker metoprolol tartrate, is used in the treatment of different diseases such as cardiac arrhythmias, hypertension, heart failure, angina pectoris, migraine, and hyperthyroidism. Beside dosage forms of the parenteral ampoule and conventional tablets of different manufacturers, there are extended release tablets of metoprolol tartrate in the Turkish Drug Market. In this research work, comparative quality control studies of metoprolol tartrate extended release tablets (original and generic) produced by two different pharmaceutical companies in the Turkey were carried out and evaluated according to the related guidelines. Thickness and diameter, hardness, weight variation, friability, content uniformity and dissolution rate were examined as quality control parameters. A new validated HPLC method for the quantification of metoprolol tartrate has been developed. An ACE column (C18, 5 μm, 250x4.6 mm) and acetonitrile:phosphate buffer (30:70, v/v) mobile phase were used for the determination of metoprolol tartrate. The tablets showed extended release for 8 hours (70.74% release from drug A, 76.87% from the drug B). Both products have acceptable hardness, friability and weight variation values. Content of the active ingredient of the tablets was consistent with label claim (99.45% for drug A and 96.45% for drug B). The dissolution data were evaluated by model dependent and model independent methods using DDSolver program. The obtained results showed that release kinetics of both drugs were well fitted with the Korsmeyer-Peppas model. [ABSTRACT FROM AUTHOR]