Effect of Itraconazole on the Pharmacokinetics of Diclofenac in Beagle Dogs

The objective of this study was to investigate the potential effect of itraconazole on the pharmacokinetics of diclofenac potassium in beagle dogs after oral coadministration. Five male beagle dogs received a single oral 50 mg dose of diclofenac potassium alone in phase I, and along with a single oral 100 mg dose of itraconazole in phase II. Blood samples obtained for 8.0 hours post dose were analysed for diclofenac concentration using a validated high performance liquid chromatography (HPLC) assay method. The area under plasma concentration-time curve (AUC0–∞), maximum plasma concentration (Cmax), time to reach Cmax (Tmax) and elimination half-life (t1/2), were calculated for diclofenac before and after itraconazole administration. The coadministration of itraconazole with diclofenac potassium has resulted in a significant reduction in AUC0–∞ and Cmax of diclofenac, which was about 31 and 42%; respectively. No statistically significant differences were observed for Tmax and t1/2 of diclofenac between the two phases. Therefore, it could be concluded that oral coadministration of itraconazole may have the potential to affect the absorption of diclofenac as indicated by the significant reduction in its AUC and Cmax in beagle dogs

Effect of Garden Cress Seeds Powder and Its Alcoholic Extract on the Metabolic Activity of CYP2D6 and CYP3A4

The powder and alcoholic extract of dried seeds of garden cress were investigated for their effect on metabolic activity of CYP2D6 and CYP3A4 enzymes. In vitro and clinical studies were conducted on human liver microsomes and healthy human subjects, respectively. Dextromethorphan was used as a common marker for measuring metabolic activity of CYP2D6 and CYP3A4 enzymes. In in vitro studies, microsomes were incubated with NADPH in presence and absence of different concentrations of seeds extract. Clinical investigations were performed in two phases. In phase I, six healthy female volunteers were administered a single dose of dextromethorphan and in phase II volunteers were treated with seeds powder for seven days and dextromethorphan was administered with last dose. The O-demethylated and N-demethylated metabolites of dextromethorphan were measured as dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Observations suggested that garden cress inhibits the formation of DOR and 3-MM metabolites. This inhibition of metabolite level was attributed to the inhibition of CYP2D6 and CYP3A4 activity. Garden cress decreases the level of DOR and 3-MM in urine and significantly increases the urinary metabolic ratio of DEX/DOR and DEX/3-MM. The findings suggested that garden cress seeds powder and ethanolic extract have the potential to interact with CYP2D6 and CYP3A4 substrates

Inhibition of cytochrome P450 enzymes by thymoquinone in human liver microsomes

The aim of the present study was to investigate the potential effect of thymoquinone (TQ) on the metabolic activity of four major drug metabolizing enzymes in human liver microsomes, namely cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6 and CYP3A4. The inhibition of CYP enzymatic activities by TQ was evaluated by incubating typical substrates (phenacetin for CYP1A2, tolbutamide for CYP2C9, dextromethorphan for CYP2D6, and testosterone for CYP3A4) with human liver microsomes and NADPH in the absence or presence of TQ (1, 10 and 100 µM). The respective metabolite of the substrate that was formed was measured by HPLC. Results of the presented study presented that the metabolic activities of all the investigated CYP enzymes, viz. CYP1A2, CYP2C9, CYP2D6 and CYP3A4, were inhibited by TQ. At 1 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 46.35%, followed by CYP2D6 (20.26%) > CYP1A2 (13.52%) > CYP3A4 (12.82%). However, at 10 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 69.69%, followed by CYP3A4 (23.59%) > CYP1A2 (23.51%) > CYP2D6 (11.42%). At 100 µM TQ, CYP1A2 enzyme activity was maximally inhibited by 81.92%, followed by CYP3A4 (79.24%) > CYP2C9 (69.22%) > CYP2D6 (28.18%). The IC50 (mean ± SE) values for CYP1A2, CYP2C9, CYP2D6 and CYP3A4 inhibition were 26.5 ± 2.9 µM, 0.5 ± 0.4 µM, >500 µM and 25.2 ± 3.1 µM, respectively. These findings suggest that there is a high probability of drug interactions resulting from the co-administration of TQ or herbs containing TQ with drugs that are metabolized by the CYP enzymes, particularly CYP2C9. Keywords: Thymoquinone, Cytochrome P450, Metabolism, Human liver microsome

Delivery of Insulin via Skin Route for the Management of Diabetes Mellitus: Approaches for Breaching the Obstacles

Insulin is used for the treatment of diabetes mellitus, which is characterized by hyperglycemia. Subcutaneous injections are the standard mode of delivery for insulin therapy; however, this procedure is very often invasive, which hinders patient compliance, particularly for individuals requiring insulin doses four times a day. Furthermore, cases have been reported of sudden hypoglycemia occurrences following multidose insulin injections. Such an invasive and intensive approach motivates the quest for alternative, more user-friendly insulin administration approaches. For example, transdermal delivery has numerous advantages, such as prolonged drug release, low variability in the drug plasma level, and improved patient compliance. In this paper, the authors summarize different approaches used in transdermal insulin delivery, including microneedles, chemical permeation enhancers, sonophoresis, patches, electroporation, iontophoresis, vesicular formulations, microemulsions, nanoparticles, and microdermabrasion. Transdermal systems for insulin delivery are still being widely researched. The conclusions presented in this paper are extracted from the literature, notably, that the transdermal route could effectively and reliably deliver insulin into the circulatory system. Consistent progress in this area will ensure that some of the aforementioned transdermal insulin delivery systems will be introduced in clinical practice and commercially available in the near future

Hydroxypropyl-β-Cyclodextrin for Delivery of Sinapic Acid via Inclusion Complex Prepared by Solvent Evaporation Method

The goal of this study was to increase the aqueous solubility and dissolution rate of sinapic acid (SA) by formulating binary inclusion complex (BIC) of SA with hydroxypropyl-β-cyclodextrin (HPβCD) using solvent evaporation (SE) technology. The phase solubility and dissolution studies were conducted to determine the solubility and in vitro release rate of SA. In addition, the prepared inclusion complex was characterized for solid state characterization using techniques such as DSC, PXRD, SEM, and FTIR. Moreover, the prepared SA-BIC was evaluated for its antioxidant activity. Results revealed that the SA solubility can be shown to improve with a change in HPβCD concentration. About 2.59 times higher solubility of SA in water was noticed in the presence of HPβCD (10 mM). Dissolution study demonstrated that the 34.11 ± 4.51% of SA was released from binary physical mixture (BPM), while the maximum release of 46.27 ± 2.79% of SA was observed for SA-BIC prepared by SE method. The prepared SA-BIC demonstrated distinctive properties when compared to pure SA, which was demonstrated by different analytical methods, such as DSC, PXRD, SEM, and FTIR, as evidence of SA inclusion into HPβCD cavity. Further, it was observed that SA-BIC displayed stronger DPPH radical scavenging activity than SA. In conclusion, SE technology considerably enhanced the complexity of SA with HPβCD, and these observations could help to heighten the SA solubility, which may lead to a better bioavailability

Formation of Leukotrienes From Calcium Ionophore-A23187 Stimulated Rabbit, Rat and Mice White Blood Cells

Leukotrienes (LTs) producing capacity was investigated in calcium ionophore A23 187- stimulated rabbit. rat and mice peripheral white blood cells suspension. A reverse phase high performance liquid chromatography technique and computerized UV spectroscopy were employed to isolate and quantitate the released LTs namely. LTC4 and LTB4. Preincubation of rabbit white blood cells at 37°C for 5 min followed by calcium ionophore-A23 187 (1 pM) stimulation for another 5 min produced an equal amounts of LTC4 as compared to LTC4 produced by human white blood cells (105±11 versus 95±9.5 pmol/107 cells respectively; mean ±SEM). In contrast rabbit white blood cells synthesized significantly lower LTB4 in comparison with LTB4 produced by peripheral white blood cells from healthy control (168±18 versus 228±19 pmol/107 cells respectively: mean ±SEM). When rat and mice white blood cells suspension were stimulated with calcium ionophore A23187 (1 µM) after preincubation at 37°C for 5 min, equivalent amounts of LTC4 and LTB4 were observed. However, LTB4 and LTC4 produced by rat and mice white blood cells were significantly lower in comparison with LTB4 and LTCj produced by human white blood cells stimulated with calcium ionophore-A23 187. These results demonstrate that rabbit. rat and mice white blood cells suspension possess the capacity to produce LTC4 and LTB4 from endogenous substrate after calcium ionophore-A23 187 stimulation

Thermodynamic Solubility Profile of Temozolomide in Different Commonly Used Pharmaceutical Solvents

The solubility parameters, and solution thermodynamics of temozolomide (TMZ) in 10 frequently used solvents were examined at five different temperatures. The maximum mole fraction solubility of TMZ was ascertained in dimethyl sulfoxide (1.35 × 10−2), followed by that in polyethylene glycol-400 (3.32 × 10−3) > Transcutol® (2.89 × 10−3) > ethylene glycol (1.64 × 10−3) > propylene glycol (1.47 × 10−3) > H2O (7.70 × 10−4) > ethyl acetate (5.44 × 10−4) > ethanol (1.80 × 10−4) > isopropyl alcohol (1.32 × 10−4) > 1-butanol (1.07 × 10−4) at 323.2 K. An analogous pattern was also observed for the other investigated temperatures. The quantitated TMZ solubility values were regressed using Apelblat and Van’t Hoff models and showed overall deviances of 0.96% and 1.33%, respectively. Apparent thermodynamic analysis indicated endothermic, spontaneous, and entropy-driven dissolution of TMZ in all solvents. TMZ solubility data may help to formulate dosage forms, recrystallize, purify, and extract/separate TMZ

Cinnamon modulates the pharmacodynamic & pharmacokinetic of amlodipine in hypertensive rats

The objective of this study was to investigate the effects of cinnamon on the pharmacodynamic (PD) & pharmacokinetic (PK) of amlodipine in hypertensive rats. The hypertensive control group of Wistar rats received L-NAME (40 mg/kg, daily, orally) only. The cinnamon group of rats was treated with cinnamon (200 mg/kg, daily, orally) along with L-NAME. Following 14 days treatment period, blood pressures of rats were monitored at designated intervals over 24 h utilizing a tail-cuff system for measuring blood pressure. To assess the oral PK; amlodipine was administered as a single oral dose of 1 mg/kg to rats and blood samples were collected at specified intervals over 24 h and analysed by UPLC-LC MS/MS.Synergistic decreased in rat’s blood pressure was observed in presence of cinnamon + amlodipine. Simultaneous administration of cinnamon ameliorates the Cmax and AUC0-t of amlodipine, the Cmax and AUC0-t was 11.04 ± 1.01 ng/ml and 113.76 ± 5.62 ng h/ml for the cinnamon + amlodipine group as compared to 4.12 ± 0.49 ng/ml and 48.59 ± 4.28 ng h/ml for the amlodipine alone group. The study demonstrates that the use of cinnamon considerably decreases the blood pressure levels and enhances the PK parameters of amlodipine in hypertensive rats