Effect of Hibiscus sabdariffa and Zingiber officinale on pharmacokinetics and pharmacodynamics of amlodipine.

OBJECTIVES: To study the effect of Zingiber officinale and Hibiscus sabdariffa on pharmacokinetics and pharmacodynamics of amlodipine. METHODS: Hypertension was induced in rats (SBP 173.2 ± 1.7 mmHg, mean, 1-24 h). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of group-I (amlodipine treated), group-II (Z. officinale, and Z. officinale + amlodipine) and group-III (H. sabdariffa, and H. sabdariffa + amlodipine) animals were measured by "tail-cuff system". Pharmacokinetics of amlodipine with and without herbs (Z. officinale or H. sabdariffa) was also investigated. RESULTS: Z. officinale as well as H. sabdariffa decreased the SBP, DBP and MBP. Concurrent treatment with Z. officinale + amlodipine (SBP 129.4 ± 4.5) or H. sabdariffa + amlodipine (SBP 130.4 ± 3.9) showed higher decrease in BP (mean, 1-24h), than individually administered amlodipine (SBP 149.5 ± 2.4) or Z. officinale (SBP 150.2 ± 3.1) or H. sabdariffa (SBP 139.1 ± 1.2). These herbs also influenced the Cmax, AUC0-t, and Tmax of amlodipine. H. sabdariffa increased AUC0-t of amlodipine from 81.8 ± 14.7 to 125.0 ± 10.6 (ng h/mL). CONCLUSION: Simultaneous administration of Z. officinale or H. sabdariffa with amlodipine, improves its pharmacodynamic response.

Effect of Nigella sativa and Fenugreek on the Pharmacokinetics and Pharmacodynamics of Amlodipine in Hypertensive Rats.

BACKGROUND: The present article is related to in-vitro and in-vivo herb-drug interaction studies. OBJECTIVES: This study aimed to investigate the effect of Nigella sativa and fenugreek on the pharmacodynamics and pharmacokinetics of amlodipine. METHOD: Hypertensive rats of group-I were treated with amlodipine and rats of group-II and III were treated with N. sativa, and N. sativa + amlodipine and fenugreek, and fenugreek + amlodipine, respectively. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) of group-I, II and III rats were measured by the "tail-cuff system". RESULTS: N. sativa, as well as fenugreek, reduced the SBP, DBP and MBP. Simultaneously, administration of fenugreek + amlodipine or N. sativa + amlodipine showed better control of BP. Individually, fenugreek, as well as N. sativa, showed a surprising reduction in the heart rate. There was no remarkable effect of any of these two herbs on Cmax, AUC0-t, Kel, and terminal elimination half-life of amlodipine, but fenugreek altered the Tmax of amlodipine significantly, from 2 ± 1.2h in control to 7.2 ± 1.7h in fenugreek treated group, probably by delaying the absorption. CONCLUSION: Results of pharmacodynamics and pharmacokinetics studies suggested that simultaneous administration of fenugreek or N. sativa with amlodipine improved the pharmacological response of amlodipine in hypertensive rats, though there was no remarkable change in pharmacokinetic parameters (Cmax, Kel, elimination t1/2, and AUC0-t).

Erratum to "Rapid, Validated UPLC-MS/MS Method for Determination of Glibenclamide in Rat Plasma".

[This corrects the article DOI: 10.1155/2018/2569027.].

A Validated Ultra-Performance Liquid Chromatography Tandem Triple Quadrupole Mass Spectrometric Method for Fast Determination of Losartan in Rabbit Plasma.

A rapid UPLC-MS-MS method was developed and validated for determination of losartan in rabbit plasma. Protonated adducts of losartan and eprosartan (IS) were monitored in multiple reaction monitoring mode. Molecular masses of daughter species of losartan were m/z 423.19 > 207 and m/z 423.19 > 180; and of eprosartan were m/z 425.11 > 135 and m/z 425.11 > 107. Losartan from plasma samples was extracted by protein precipitation method. The mobile phase comprising water (0.1% formic acid) (A) and acetonitrile (0.1% formic acid) (B) was used in gradient mode. Analytes were eluted on Acquity UPLC®BEH C18 1.7 µm, 2.1 × 50 mm column. Sample run time was 3.0 min. The validation parameters: accuracy, precision and recovery were within recommended limits. Losartan as well as internal standard remains stable in benchtop stability study as well as in post-preparative stability study. Pharmacokinetic parameters such as Cmax (182.79 ± 23.80 ng/mL), Tmax (1.16 ± 0.28 h), AUC0-t (1188.57 ± 404.60 ng h/mL) and Kel (0.0954 ± 0.0140 h-1) of losartan were measured. Method was successfully applied for pharmacokinetic investigation in rabbits and can be used for losartan determination in plasma sample obtained from other animals.

Rapid, Validated UPLC-MS/MS Method for Determination of Glibenclamide in Rat Plasma.

Quick and specific bioanalytical methods are required for analyzing drugs in biological samples. A simple, quick, sensitive, and specific UPLC-MS/MS method was developed and validated for glibenclamide determination in plasma samples. The plasma samples were processed by protein precipitation technique. Glimepiride was used as internal standard (IS). Glibenclamide and glimepiride were eluted on C18 column (Acquity UPLC®BEH). Mobile phase consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid) was pumped in binary gradient mode at flow rate of 150 µL/min. Glibenclamide and IS elution time was about 1.0 min, and total run time was 2.0 min. The mass spectrometer (triple-quadrupole) was operated in positive electrospray ionization mode. Sodium adducts [M + Na]+ of glibenclamide and IS were monitored in MRM mode. A linear calibration curve was obtained in the range of 10-1280 ng/mL, with regression equation Y = 0.0076 X - 0.0165 and linear regression coefficient r2 = 0.999. Lower limit of quantitation was 10 ng/mL. Accuracy of the method at LQC, MQC, and HQC was 109.7% (± 6.7), 93.6% (± 0.4), and 99.3% (± 1.9), respectively. The coefficient of variation for precision at all QC concentrations was less than 6%. Recovery at LLQC, MQC, and HQC was 104.2% (± 4.9), 100.6% (± 0.9), and 102.9% (± 5.8), respectively. The method was successfully implemented for pharmacokinetic investigations (in-house data).

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

CONTEXT: Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. OBJECTIVE: Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. METHODS: Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. RESULTS: This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. CONCLUSION: The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Pharmacokinetic interaction of Acacia catechu with CYP1A substrate theophylline in rabbits.

OBJECTIVE: To investigate the effect of black catechu (BC) on the pharmacokinetics of theophylline (CYP1A2 substrate, with narrow therapeutic index) in rabbits. METHODS: In the present investigation the effect of BC on the pharmacokinetics of theophylline, a CYP1A2 substrate was determined. In the study, BC (264 mg/kg, p. o.) or saline (control group) was given to rabbits for 7 consecutive days and on the 8th day theophylline (16 mg/kg) was administered orally one hour after BC or saline treatment. Blood samples were withdrawn at different time intervals (0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from the marginal ear vein. RESULTS: The pretreatment of rabbits with BC resulted in a significant increase in maximum blood concentration, time of peak concentration and area under the concentration time profile curve until last observation which was about 41.32%, 35.71% and 15.03%, respectively. While decreases in clearance, volume of distribution, and half-life were observed. It is suggested that BC pretreatment decreases the CYP1A metabolic activity leading to increase in bioavailability and decrease in oral clearance of theophylline, which may be due to inhibition of CYP1A. CONCLUSION: BC can significantly alter theophylline pharmacokinetics in vivo possibly due to inhibition of CYP1A and P-glycoprotein activity. Based on these results, precaution should be exercised when administering BC with CYP1A substrate.

Rhodamine-123: a p-glycoprotein marker complex with sodium lauryl sulfate.

Aim of this study was to investigate the role of sodium lauryl sulfate (SLS) as P-glycoprotein inhibitor. The everted rat gut sac model was used to study in-vitro mucosal to serosal transport of Rhodamine-123 (Rho-123). Surprisingly, SLS decreases the serosal absorption of Rho-123 at all investigated concentrations. Investigation reveals complex formation between Rhodamine-123 and sodium lauryl sulfate. Interaction profile of SLS & Rho-123 was studied at variable SLS concentrations. The SLS concentration higher than critical micelle concentration (CMC) increases the solubility of Rho-123 but could not help in serosal absorption, on the contrary the absorption of Rho-123 decreased. Rho-123 and SLS form pink color complex at sub-CMC. The SLS concentrations below CMC decrease the solubility of Rho-123. For further studies, Rho-123 & SLS complex was prepared by using solvent evaporation technique and characterized by using differential scanning calorimeter (DSC). Thermal analysis also proved the formation of complex between SLS & Rho-123. The P values were found to be significant (<0.05) except group comprising 0.0001% SLS, and that is because 0.0001% SLS is seems to be very low to affect the solubility or complexation of Rho-123.

Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects.

Effect of Curcuma longa rhizome powder and its ethanolic extract on CYP2D6 and CYP3A4 metabolic activity was investigated in vitro using human liver microsomes and clinically in healthy human subjects. Dextromethorphan (DEX) was used as common probe for CYP2D6 and CYP3A4 enzymes. Metabolic activity of CYP2D6 and CYP3A4 was evaluated through in vitro study; where microsomes were incubated with NADPH in presence and absence of Curcuma extract. In clinical study phase-I, six healthy human subjects received a single dose (30 mg) of DEX syrup, and in phase-II DEX syrup was administered with Curcuma powder. The enzyme CYP2D6 and CYP3A4 mediated O- and N-demethylation of dextromethorphan into dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Curcuma extract significantly inhibited the formation of DOR and 3-MM, in a dose-dependent and linear fashion. The 100 µg/ml dose of curcuma extract produced highest inhibition, which was about 70 % for DOR and 80 % for 3-MM. Curcuma significantly increases the urine metabolic ratio of DEX/DOR but the change in DEX/3-MM ratio was statistically insignificant. Present findings suggested that curcuma significantly inhibits the activity of CYP2D6 in in vitro as well as in vivo; which indicates that curcuma has potential to interact with CYP2D6 substrates.

Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates.

INTRODUCTION: Present article reviews solid dispersion (SD) technologies and other patented inventions in the area of pharmaceutical SDs, which provide stable amorphous SDs. AREAS COVERED: The review briefly compiles different techniques for preparing SDs, their applications, characterization of SDs, types of SDs and also elaborates the carriers used to prepare SDs. The advantages of recently introduced SD technologies such as RightSize(™), closed-cycle spray drying (CSD), Lidose® are summarized. Stability-related issues like phase separation, re-crystallization and methods to curb these problems are also discussed. A patented carrier-screening tool for predicting physical stability of SDs on the basis of drug-carrier interaction is explained. Applications of SD technique in controlled drug delivery systems and cosmetics are explored. Review also summarizes the carriers such as Soluplus®, Neusilin®, Solumer(TM) used to prepare stable amorphous SD. EXPERT OPINION: Binary and ternary SDs are found to be more stable and provide better enhancement of solubility or dissolution of poorly water-soluble drugs. The use of surfactants in the carrier system of SD is a recent trend. Surfactants and polymers provide stability against re-crystallization of SDs, surfactants also improve solubility and dissolution of drug.

Everted gut sac model as a tool in pharmaceutical research: limitations and applications.

OBJECTIVES: This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction. KEY FINDINGS: The mechanism of drug absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also. SUMMARY: The everted sac model is an efficient tool for studying in-vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.