Concentration profiles and safety of topically applied betulinic acid and NVX-207 in eight healthy horses-A randomized, blinded, placebo-controlled, crossover pilot study.

The naturally occurring betulinic acid (BA) and its derivative NVX-207 show anticancer effects against equine malignant melanoma (EMM) cells and a potent permeation in isolated equine skin in vitro. The aim of the study was to determine the in vivo concentration profiles of BA and NVX-207 in equine skin and assess the compounds' local and systemic tolerability with the intent of developing a topical therapy against EMM. Eight horses were treated percutaneously in a crossover design with 1% BA, 1% NVX-207 or a placebo in a respective vehicle twice a day for seven consecutive days with a seven-day washout period between each formulation. Horses were treated at the neck and underneath the tail. Concentration profiles of the compounds were assessed by high-performance liquid chromatography in the cervical skin. Clinical and histopathological examinations and blood analyses were performed. Higher concentrations of NVX-207 were found in the skin compared to BA. Good systemic tolerability and only mild local adverse effects were observed in all three groups. This study substantiates the topical application of BA and NVX-207 in further clinical trials with horses suffering from EMM; however, penetration and permeation of the compounds may be altered in skin affected by tumors.

Drug-Drug Interactions of P-gp Substrates Unrelated to CYP Metabolism.

BACKGROUND: Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs. OBJECTIVE: Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies. CONCLUSION: Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.

High-throughput LC-MS/MS method with 96-well plate precipitation for the determination of arotinolol and amlodipine in a small volume of rat plasma: Application to a pharmacokinetic interaction study.

A rapid, sensitive, and selective liquid chromatography with tandem mass spectrometry method was developed and fully validated for the simultaneous quantification of arotinolol and amlodipine in rat plasma. Two internal standards were introduced with metoprolol as the internal standard of arotinolol and (S)-amlodipine-d4 as the internal standard of amlodipine. The analytes were isolated from 50.0 µL plasma samples by a simple protein precipitation using acetonitrile. The chromatographic separation was achieved in 5 min on a C18 column. The mobile phase consisted of phase A 5% methanol and phase B 95% methanol (both containing 0.5% formic acid and 5 mM ammonium acetate) and was delivered in gradient elution at 0.300 mL/min. Quantification was performed in multiple reaction monitoring mode with the transition m/z 372.1 â†’ 316.1 for arotinolol, m/z 268.2 â†’ 116.2 for metoprolol, m/z 409.1 â†’ 238.1 for amlodipine and m/z 413.1 â†’ 238.1 for (S)-amlodipine-d4. Linearity was obtained over the range of 0.200-40.0 ng/mL for arotinolol (r2  = 0.9988) and 0.500-100 ng/mL for amlodipine (r2  = 0.9985) in rat plasma. The validated data have met the acceptance criteria in FDA guideline. This method was successfully applied to a pharmacokinetic interaction study in rats, and the results indicated that there was no significant drug-drug interaction between arotinolol and amlodipine.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

The Pharmacokinetic Interaction Study between Carvedilol and Bupropion in Rats.

BACKGROUND/AIMS: The effects of multiple-dose bupropion on the pharmacokinetics of single-dose carvedilol were investigated in order to evaluate this possible drug-drug interaction. METHODS: A preclinical study was conducted among white male Wistar rats. Each rat was cannulated on the femoral vein prior to being connected to BASi Culex ABC®. During the reference period, each rat received an intravenous and an oral dose of 3.57 mg/kg body weight (b.w.) carvedilol, at 2 days distance. After 5 days of pretreatment with 21.42 mg/kg b.w. bupropion (by oral route, twice a day - given in order to reach the steady state), during the sixth day, 3.57 mg/kg b.w. carvedilol and 21.42 mg/kg b.w. bupropion were orally co-administrated (test period). After each administration of carvedilol, several samples of 200 µL blood were collected. The pharmacokinetic parameters of carvedilol were analyzed by the noncompartmental method. RESULTS: The 5 days pretreatment with bupropion increased the exposure to carvedilol in rats by 180%, considering the modifications observed in the area under the curve of carvedilol. Carvedilol was shown to have higher plasma concentrations, delay in maximum concentration, and a prolonged half-life, after being pretreated with bupropion. CONCLUSION: The administration of multiple-dose bupropion influences the pharmacokinetics of carvedilol (single oral dose) in rats.

Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group.

PURPOSE: The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective ß1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. MATERIALS AND METHODS: We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. FINDINGS: Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol (p < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. IMPLICATIONS: Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. TRIAL REGISTRATION: NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7.

Antifibrotic Effects of Carvedilol and Impact of Liver Fibrosis on Carvedilol Pharmacokinetics in a Rat model.

BACKGROUND AND OBJECTIVES: Carvedilol is a drug of choice in treatment of portal hypertension. The present study was designed to elucidate the potential role of antifibrotic effects of carvedilol in improving hepatic efficiency and the carvedilol oral pharmacokinetic changes during induction of liver fibrosis. METHODS: Rats were given CCl4 (1 ml/kg, intraperitoneal) twice weekly for 6 weeks and/or co-treated with carvedilol (10 mg/kg, orally) three times weekly on alternating days. Indocyanine green (ICG) clearance test was used as a modality for the measurement of hepatic blood flow. In addition, assessment of serum albumin as a marker of synthetic capacity and immunohistochemical staining of P-glycoprotein (P-gp) expression as a marker of metabolic capacity were done. Furthermore, hydroxyproline and TGF-ß1 were detected as markers of liver fibrosis. RESULTS: The area under plasma concentration-time curve of a single dose of carvedilol was significantly increased, associated with decreased the clearance in rats intoxicated with CCl4 compared to control group. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks significantly counteracted the changes in hepatotoxicity markers and histopathological lesions induced by CCl4. In addition, there were no significant alterations in carvedilol pharmacokinetics between control and CCl4-intoxicated rats. Furthermore, carvedilol treatment restored liver efficiency, including synthetic and metabolic capacity as well as hepatic blood flow. CONCLUSION: The present study provides evidence underlying the antifibrotic effects of carvedilol and enhancement of hepatic efficiency. In addition, the pharmacokinetic parameters of a single dose of carvedilol are altered in liver fibrosis, manifested as delayed clearance. This was attributed to the reduction of both hepatic blood flow and CYP2D6 expression in the liver. Carvedilol co-treatment in CCl4-intoxicated rats for 6 weeks recovered its pharmacokinetic profile, which is mainly attributed to the impact of pharmacodynamic antifibrotic effects of carvedilol on its own kinetics.

The Effect of Apatinib on the Metabolism of Carvedilol Both in vitro and in vivo.

BACKGROUND: In light of the growing number of cancer survivors, the incidence of cardiovascular complications in these patients had also increased, while the effect of apatinib on the pharmacokinetic of cardioprotective drug (carvedilol) in rats or human is still unknown. The present work was to study the impact of apatinib on the metabolism of carvedilol both in vitro and vivo. METHODS: A specific and sensitive ultra-performance liquid-chromatography tandem mass spectrometry method was applied to determine the concentration of carvedilol and its metabolites (4'-hydroxyphenyl carvedilol [4'-HPC], 5'-hydroxyphenyl carvedilol [5'-HPC] and o-desmethyl carvedilol [o-DMC]). RESULTS: The inhibition ratios in human liver microsomes were 10.28, 10.89 and 5.94% for 4'-HPC, 5'-HPC and o-DMC, respectively, while in rat liver microsomes, they were 3.22, 1.58 and 1.81%, respectively. The data in vitro of rat microsomes were consistent with the data in vivo that the inhibition of 4'-HPC and 5'-HPC formation was higher than the control group. CONCLUSION: Our study showed that apatinib could significantly inhibit the formation of carvedilol metabolites both in human and rat liver microsomes. It is recommended that the effect of apatinib on the metabolism of carvedilol should be noted and carvedilol plasma concentration should be monitored.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

High-dose short-term administration of naringin did not alter talinolol pharmacokinetics in humans.

Naringin is considered the major causative ingredient of the inhibition of intestinal drug uptake by grapefruit juice. Moreover, it is contained in highly dosed nutraceuticals available on the market. A controlled, open, randomized, crossover study was performed in 10 healthy volunteers to investigate the effect of high-dose naringin on the bioavailability of talinolol, a substrate of intestinal organic anion-transporting polypeptide (OATP)-mediated uptake. Following 6-day supplementation with 3 capsules of 350 mg naringin daily, 100mg talinolol were administered orally with 3 capsules of the same dietary supplement (1050 mg naringin) on the seventh day. This test treatment was compared to 100mg talinolol only (control). The results showed that short-term high-dose naringin supplementation did not significantly affect talinolol pharmacokinetics. Geometric mean ratios of test versus control ranged between 0.90 and 0.98 for talinolol c(max), AUC(0-48 h), AUC(0-∞), t(1/2) and A(e(0-48 h)). The high dose may provoke inhibition of the efflux transporter P-glycoprotein (P-gp) which counteracts the uptake inhibition. As disintegration and dissolution processes are required for the solid dosage form, dissolved naringin may arrive at the site of interaction after talinolol is already absorbed. In conclusion, the effect of nutraceuticals on drug pharmacokinetics can deviate from that observed when administered as food component due to the different dose and dosage form.

Controlled delivery of carvedilol nanosuspension from osmotic pump capsule: in vitro and in vivo evaluation.

This study intended to develop a novel controlled delivery osmotic pump capsule of carvedilol nanosuspension. The capsule is assembled using a semi-permeable capsule shell with contents including nanosuspension drying powder, mannitol and Plasdone S-630. The physical characteristics of semi-permeable capsule walls were compared among different coating solutions under different temperature. The composition of the coating solution and drying temperature appeared to be important for the formation of the shells. Carvedilol nanosuspension was prepared by precipitation-ultrasonication technique and was further lyophilized. Response surface methodology was used to investigate the influence of factors on the responses. The optimized formulation displayed complete drug delivery and zero-order release rate. The TEM and particle size analysis indicated that the morphology of the resultant nanoparticle in the capsule was spherical shaped with a mean size of 252±19 nm. The in vivo test in beagle dogs demonstrated that the relative bioavailability of the novel system was 203.5% in comparison to that of the marketed preparation. The capsule successfully controlled the release of carvedilol and the fluctuation of plasma concentration was minimized. The system is a promising strategy to improve the oral bioavailability for poorly soluble drugs and preparing it into elementary osmotic pump conveniently.

In vitro pharmacological characterization of vilanterol, a novel long-acting ß2-adrenoceptor agonist with 24-hour duration of action.

Vilanterol trifenatate (vilanterol) is a novel, long-acting ß(2)-adrenoceptor (ß(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize ß(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the ß(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for ß(2)- over ß(1)-AR and ß(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective ß(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).

Chronically lowering sympathetic activity protects sympathetic nerves in spleens from aging F344 rats.

In the present study, we investigated how increased sympathetic tone during middle-age affects the splenic sympathetic neurotransmission. Fifteen-month-old (M) F344 rats received rilmenidine (0, 0.5 or 1.5mg/kg/day, i.p. for 90 days) to lower sympathetic tone. Controls for age were untreated 3 or 18M rats. We report that rilmenidine (1) reduced plasma and splenic norepinephrine concentrations and splenic norepinephrine turnover, and partially reversed the sympathetic nerve loss; and (2) increased ß-adrenergic receptor (ß-AR) density and ß-AR-stimulated cAMP production. Collectively, these findings suggest a protective effect of lowering sympathetic tone on sympathetic nerve integrity, and enhanced sympathetic neurotransmission in secondary immune organs.

Clinical pharmacokinetics and therapeutic efficacy of esmolol.

Esmolol is a unique cardioselective ß(1)-receptor blocking agent with a rapid onset and short duration of action. Since our previous review in 1995, the pharmacokinetics and efficacy of esmolol have been investigated in a number of acute care settings. Three studies investigated the pharmacokinetics and safety of esmolol in the paediatric population. The disposition of esmolol in children was found to be linear with plasma concentrations increasing in proportion to dose over the ranges studied. The pharmacokinetic estimates for esmolol showed a shorter elimination half-life (t(½)) [2.7-4.8 minutes] and a higher clearance (281 mL/kg/min) in newborns and infants than that found in children (>2 years old) and adults. Dosing requirements to achieve targeted blood pressure in post-coarctectomy patients were substantially higher (mean 700 µg/kg/min) than that used in adults. Esmolol was effective in controlling hypertension following cardiac surgery and terminating supraventricular arrhythmias in children. The efficacy of esmolol has been established in a variety of patients, including those with unstable angina, myocardial ischaemia, supraventricular arrhythmias, peri- and postoperative tachycardia and hypertension, and electroconvulsive therapy. With careful titration and monitoring, esmolol can be used effectively in patients with congestive heart failure and chronic obstructive lung disease because of its unique short t(½) and ß(1)-selectivity. Different dosage schedules have been developed depending on clinical setting and diagnosis. Generally, a loading dose of ≤500 µg/kg/min over 1 minute is administered followed by a continuous infusion of 25-300 µg/kg/min. Hypotension, being the primary adverse effect, can be minimized by careful dosage titration and patient monitoring. In the perioperative setting involving tracheal intubation and extubation, a number of recent studies have suggested that titration of esmolol to a haemodynamic endpoint can be safe and effective, resulting in a decreased incidence of myocardial ischaemia. The most effective regimen in attenuating the response to heart rate and blood pressure after laryngeal tracheal intubation was a loading dose of 500 µg/kg/min for 4 minutes followed by a continuous infusion of 200-300 µg/kg/min. In cardiac and non-cardiac surgical patients esmolol has been shown to decrease episodes of myocardial ischaemia and arrhythmias. In the perioperative period for non-cardiac surgery routine use of ß-blockers (ß-adrenoceptor antagonists) is no longer recommended. However, in patients at high risk for myocardial ischaemia or undergoing high-risk surgery where a ß-blocker is indicated, esmolol is the ideal perioperative agent to minimize the risk of hypotension and bradycardia based on its pharmacodynamic and pharmacokinetic characteristics. For postoperative patients in atrial fibrillation, esmolol achieves rapid ventricular rate control. However, for the prevention of postoperative atrial fibrillation esmolol provides no advantage over oral ß-blockers. In other situations where emergent ß-blockade is required, such as electroconvulsive therapy, esmolol has been shown to effectively control haemodynamic response. After more than 2 decades of use esmolol continues to provide an important therapeutic option in the acute care setting.

Effects of myricetin on the bioavailability of carvedilol in rats.

CONTEXT: As an inhibitor of CYP2C9, CYP2D6 and P-gp, myricetin might affect the bioavailability of carvedilol when myricetin and carvedilol are used concomitantly for the prevention or therapy of cardiovascular diseases as a combination therapy. However, the effect of myricetin on the pharmacokinetics of carvedilol has not been reported in vivo. OBJECTIVE: This study investigated the effects of myricetin on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. MATERIALS AND METHODS: Carvedilol was administered orally or intravenously with or without oral administration of myricetin to rats. RESULTS: The effects of myricetin on P-gp, CYP2C9 and 2D6 activity were evaluated. Myricetin inhibited CYP2C9 and CYP2D6 enzyme activity with IC50 of 13 and 57 µM, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the AUC was significantly increased by 52.0-85.1%, and the C(max) was significantly increased by 93.1-133.4% in the presence of myricetin after oral administration of carvedilol. Consequently, the relative bioavailability of carvedilol was increased by 1.17- to 1.85-fold and the absolute bioavailability of carvedilol in the presence of myricetin was increased by 18.1-86.4%. T(max) was significantly decreased. DISCUSSION AND CONCLUSION: The enhanced oral bioavailability of carvedilol may result from both inhibition of CYP2C9 or CYP2D6-mediated metabolism and P-gp-mediated efflux of carvedilol in small intestine and/or in liver by myricetin rather than reducing renal elimination. Concomitant use of myricetin or myricetin-containing dietary supplements with carvedilol will require close monitoring for potential drug interactions.

Comparative study on the effects of some polyoxyethylene alkyl ether and sorbitan fatty acid ester surfactants on the performance of transdermal carvedilol proniosomal gel using experimental design.

The aim of this work was to investigate the effects of formulation variables on development of carvedilol (CAR) proniosomal gel formulations as potential transdermal delivery systems. Different non-ionic surfactants; polyoxyethylene alkyl ethers, namely Brij 78, Brij 92, and Brij 72; and sorbitan fatty acid esters (Span 60) were evaluated for their applicability in preparation of CAR proniosomal gels. A 2(3) full factorial design was employed to evaluate individual and combined effects of formulation variables, namely cholesterol content, weight of proniosomes, and amount of CAR added on performance of proniosomes. Prepared proniosomes were evaluated regarding entrapment efficiency (EE%), vesicle size, and microscopic examination. Also, CAR release through cellulose membrane and permeation through hairless mice skin were investigated. Proniosomes prepared with Brij 72 and Span 60 showed better niosome forming ability and higher EE% than those prepared with Brij 78 and Brij 92. Higher EE% was obtained by increasing both weight of proniosomes and amount of CAR added, and decreasing cholesterol content. Release rate through cellulose membrane was inversely affected by weight of proniosomes. In Span 60 proniosomes, on increasing percent of cholesterol, a decrease in release rate was observed. While in Brij 72 proniosomes, an enhancement in release rate was observed on increasing amount of CAR added. Permeation experiments showed that skin permeation was mainly affected by weight of proniosomes and that Span 60 proniosomal gels showed higher permeation enhancing effect than Brij 72. Proniosomal gel could constitute a promising approach for transdermal delivery of CAR.

Pre-clinical evidence of enhanced oral bioavailability of the P-glycoprotein substrate talinolol in combination with morin.

Most known interactions between herbal extracts and drugs involve the inhibition of drug-metabolizing enzymes, but little is yet known about the possible role of transporters in these interactions. In order to evaluate the effect of one of such prominent flavonoids, morin, on P-glycoprotein related efflux carriers, measurements of transport characteristics through Ussing chambers, in situ perfusion and in vivo drug absorption studies were performed with the transported, yet not metabolized model compound talinolol.This study investigated the effects of orally administered morin (1.0, 2.5 and 5.0 mg kg(-1)), on the pharmacokinetics of orally (10 mg kg(-1)) and intravenously (1.0 mg kg(-1)) administered talinolol in rats. In the presence of morin, the pharmacokinetic parameters of talinolol were significantly altered in the oral group but not in the intravenous group. The presence of 2.5 and 5.0 mg kg(-1) of morin significantly increased (1.8-2.0 fold, p<0.01) the area under the plasma concentration-time curve and the peak plasma concentration (2.3-3.0 fold, p<0.01) of orally administered talinolol. The absolute bioavailability (F %) of talinolol in the rats pretreated with morin was significantly higher (89.09-98.29%, p<0.01) than the control (52.14%). Talinolol demonstrated asymmetric transport across rat ileum with significantly greater basolateral-to-apical (B-A) permeability than that in the apical-to-basolateral (A-B) direction. The addition of morin resulted in a concentration dependent effect, especially on the secretory transport of talinolol.The present study demonstrates that morin bears the ability to interfere with secretory intestinal transport processes. This might be due to an interaction with P-glycoprotein.

In vitro and in vivo evaluation of the effects of duloxetine on P-gp function.

OBJECTIVE: To evaluate the effect of duloxetine (DLX) on the P-glycoprotein (P-gp) function in vitro and in vivo. METHOD: In vitro experiment was conducted using the Caco-2 cell, a human colon cancer cell line that naturally expresses the P-gp and P-gp function was evaluated by monitoring whether DLX affect the accumulation of Rhd123. In vivo study was conducted by quantitating the effect of orally administered DLX on the bioavailability of talinolol. RESULTS: In the in vitro study, incubation of Caco-2 cell with DLX caused a concentration-dependent increase in the accumulation of Rhd123. In the in vivo study, co-administration of DLX increased the bioavailability of talinolol. The ratio (90% confidence intervals) of AUC(0-60), AUC(0-∞), and C(max) (talinolol alone versus talinolol plus DLX) were 0.87(0.77-1.06), 0.85(0.74-1.01), 0.87 (0.68-1.12). CONCLUSION: Our results suggest that DLX could inhibit the function of P-gp in vitro and in vivo, and caution should be exercised when DLX is to be co-administered with drugs that are P-gp substrate.