Food–drug interactions: Effect of capsaicin on the pharmacokinetics of simvastatin and its active metabolite in rats

Capsaicin (trans-8-methy-N-vanilly-6-nonenamide, CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. However, little is known about the metabolic interactions between CAP and clinically used drugs. This study attempted to investigate the effect of CAP on the pharmacokinetics of simvastatin (SV), a cytochrome P450 (CYP) 3A substrate and an important cholesterol-lowering agent. CAP (3, 8 or 25 mg/kg), ketoconazole, dexamethasone or 5% CMC-Na was given to rats for seven consecutive days and on the seventh day SV (80 mg/kg) was administered orally. The results showed that when a single dose of SV was administered to rats fed with CAP over one week, AUC_0→∞, C_max of SV and its acid metabolite was significantly decreased in comparison to the control treatment. Pretreatment of rats with CAP resulted in an decrease in the AUC_0–∞ of SV of about 67.06% (CAP 3 mg/kg, P < 0.05), 73.21% (CAP 8 mg/kg, P < 0.01) and 77.49% (CAP 25 mg/kg, P < 0.01) compared with the control group. The results demonstrate that chronic ingestion of high doses of CAP will decrease the bioavailability of SV to a significant extent in rats.     

Effects of nifedipine on the pharmacokinetics of repaglinide in rats: Possible role of CYP3A4 and P-glycoprotein inhibition by nifedipine

BackgroundThe aim of this study was to investigate the effects of nifedipine on the bioavailability and pharmacokinetics of repaglinide in rats.MethodsThe effect of nifedipine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of nifedipine (1 and 3 mg/kg).ResultsAdministration of nifedipine resulted in inhibition CYP3A4 activity with an IC₅₀ value of 7.8 μM, and nifedipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, nifedipine significantly increased the area under the plasma concentration-time curve (AUC_0–∞) and the peak plasma concentration (C_max) of repaglinide by 49.3 and 25.5%, respectively. Nifedipine significantly decreased the total body clearance (CL/F) of repaglinide by 22.0% compared to the oral control group. Nifedipine also increased the absolute bioavailability (AB) of repaglinide by 50.0% compared to the oral control group (33.6%). In addition, the relative bioavailability (RB) of repaglinide was 1.16- to 1.49-fold greater than that of the control group. Compared to the intravenous control, nifedipine significantly increased AUC_0–∞ of repaglinide. Blood glucose concentrations had significant differences compared to the oral control groups.ConclusionNifedipine enhanced the oral bioavailability of repaglinide, which may be mainly attributable to inhibition of CYP3A4-mediated metabolism of repaglinide in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine and/or reduction of total body clearance by nifedipine. The current study has raised awareness of potential drug interactions by concomitant use of repaglinide with nifedipine.     

Modulation of mdr1a and CYP3A gene expression in the intestine and liver as possible cause of changes in the cyclosporin A disposition kinetics by dexamethasone

We investigated the effect of dexamethasone (DEX) on the disposition kinetics of cyclosporin A (CyA) and the mechanism of this drug interaction. Rats were treated with DEX (1 or 75mg/kg per day, i.p.) once a day for 1-7 days, and the blood concentration of CyA was measured after an i.v. or p.o. dose of CyA (10mg/kg) at 1.5hr after the last DEX treatment. In rats treated with a low dose of DEX (1mg/kg), the blood concentration of CyA after i.v. administration was unchanged compared with that of untreated rats, whereas the blood concentration after oral administration was significantly decreased, and this decrease was dependent on the duration of DEX administration. The total clearance (CL(tot)) of CyA was unchanged, but the bioavailability was significantly decreased to about one-third of that in DEX-untreated rats after 7 days of DEX treatment. At this time, the expression of mdr1a mRNA and P-gp in the liver and intestine was increased, whereas CYP3A2 was unaffected at both the mRNA and protein levels. In rats treated with a high dose of DEX (75mg/kg), the blood concentration of CyA was significantly decreased after both i.v. and p.o. administrations compared with those of untreated rats. The bioavailability of CyA was decreased, and the CL(tot) was significantly increased. The P-gp and CYP3A2 in the liver and intestine were increased at both the mRNA and protein levels. Our results indicate that the drug interaction between CyA and DEX is a consequence of modulation of P-gp and CYP3A2 gene expression by DEX, with differential dose-dependence.     

Influence of atorvastatin on the pharmacokinetics and pharmacodynamics of glyburide in normal and diabetic rats

Atorvastatin is a selective HMG-CoA reductase competitive inhibitor, used for the treatment of hyperlipidaemia. It is metabolized by CYP 3A4 and 3A5 isoenzymes in liver. It also has moderate inhibition on metabolizing enzymes like CYP 2C9, 2D6 and 3A4. Hence there is more possibility of atorvastatin for inhibition of metabolism of glyburide, by both CYP 2C9 and 3A4. We have studied the effects of atorvastatin on the pharmacodynamics and pharmacokinetics of glyburide in experimental diabetic rats. Atorvastatin (20 mg/kg p.o.) was given to alloxan-induced diabetic rats for 7 consecutive days followed by glyburide (10 mg/kg p.o.). In the rats co-treated with atorvastatin and glyburide, fasting plasma glucose concentration (60.69 ± 5.70%) was further reduced, markedly as compared with glyburide-treated animals. In co-treated group, the pharmacokinetic parameters like clearance (27.83 ± 3.55 l/h) of glyburide was reduced, while peak plasma concentration (18.39 ± 5.29 μg/ml), area under the plasma concentration time curve (120.02 ± 15.17 μg/ml/h) and elimination half-life (4.09 ± 0.50 h) were significantly increased when compared to glyburide alone administered rats. The results of this study revealed that atorvastatin led to the PK/PD changes have been due to glyburide increased bioavailability, decrease volume of distribution, and/or decrease total clearance may be due to the inhibition of cytochrome P450 metobolic system.     

Effect of strychnine hydrochloride on liver cytochrome P450 mRNA expression and monooxygenase activities in rat

Strychnos nux-vomica L. has been frequently used in traditional Chinese medicine but has high acute toxicity. It is commonly taken with Glycyrrhizae radix to decrease its toxicity but the mechanism of this interaction is unknown. In this work, the mRNA expression and the activity of four cytochrome P450 (CYP) enzymes representative of four subfamilies (CYP1A, CYP3A, CYP2C and CYP2E) were determined ex vivo in rat livers from groups of Wistar rats orally administered strychnine hydrochloride (SH) at three doses (0.1, 0.3 and 0.9 mg/kg/day) alone and, at the highest dose, in combination with glycyrrhetinic acid (GA, 25 mg/kg/day) or liquiritin (LQ, 20 mg/kg/day) once a day for 7 consecutive days. Compared to control, the mRNA expressions of CYP3A1, 1A2 and 2E1 were higher in rats receiving the highest dose of SH but lower for CYP3A1 and CYP2E1 in rats receiving the SH+GA and SH+LQ combinations. CYP2E1 activity was higher and CYP2C, CYP3A and CYP1A2 activities were lower in rats receiving the highest dose of SH. In contrast CYP1A2 and CYP2C activities were higher and CYP2E1 and CYP3A activities lower in rats receiving the SH+GA combination. CYP2E1 and CYP3A activities were also lower in rats receiving the SH+LQ combination. The results show that treatment with SH for 7 days affects the expression and the activity of CYP enzymes and that coadministration of GA and LQ modulates these effects. This modulation may explain the role of Glycyrrhizae radix in reducing the acute toxicity of Strychnos nux-vomica L.CYPs enzymes.     

Developmental toxicity of hexachloronaphthalene in Wistar rats. A role of CYP1A1 expression

Hexachloronaphthalene (HxCN) is one of the most toxic congeners of polychlorinated naphthalenes (PCNs). This study assesses the prenatal toxicity of HxCN after daily administration at doses of 0.1–1.0 mg/kg b.w. to pregnant Wistar rats during organogenesis. We evaluated also the expression of CYP1A1 mRNA and protein in the livers of dams and fetuses, as well as the placenta. The results indicate that 0.3 mg/kg b.w. was the lowest HxCN toxic dose for dams (LOAEL) while a dose of 0.1 mg/kg b.w. was sufficient to impair the intrauterine development of embryos/fetuses without maternal toxicity. Regardless of the applied dose, HxCN generated embryotoxic effects. Dose-dependent fetotoxic effects were associated with HxCN exposure. HxCN was found to be a strong inducer of maternal and fetal CYP1A1. Expression of CYP1A1 mRNA in the placenta appears to be the most sensitive marker of HxCN exposure.     

Effect of classic and atypical neuroleptics on cytochrome P450 3A (CYP3A) in rat liver

BackgroundCytochrome P450 3A (CYP3A) subfamily is involved in the metabolism of xenobiotics (e.g., drugs) and endogenous substances (e.g., steroids). The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the level and activity of CYP3A in rat liver, measured as a rate of testosterone 2β- and 6β-hydroxylation.MethodsThe reactions were studied in control liver microsomes in the presence of neuroleptics, as well as in the microsomes of rats treated intraperitoneally (ip) with pharmacological doses of the drugs (promazine and thioridazine 10 mg/kg; chlorpromazine 3 mg/kg; haloperidol 0.3 mg/kg; risperidone 0.1 mg/kg; sertindole 0.05 mg/kg) for one day or two weeks (twice a day), in the absence of the neuroleptics in vitro.ResultsThe investigated neuroleptics added in vitro to control liver microsomes produced a moderate or week inhibitory effects on CYP3A activity. After one-day exposure of rats to neuroleptics, only chlorpromazine significantly increased the activity of CYP3A. Chronic treatment of rats with thioridazine diminished the protein level and activity of CYP3A, while risperidone induced this enzyme.ConclusionThe observed changes in the CYP3A expression after prolonged exposition to neuroleptics suggest their influence on the enzyme regulation.     

Effect of natamycin on cytochrome P450 enzymes in rats

Natamycin is a polyene macrolide antibiotic widely used in the food industry as a feed additive to prevent mold contamination of foods. There are many contradictory results on the genotoxic effects of macrolides which could suggest a potential risk for humans. In the present study, the effects of natamycin on the activities of some drug metabolizing enzymes in rat liver microsomes were determined in vivo. Rats were treated orally with natamycin at doses of 0.3, 1, 3 and 10 mg/kg body weight (bw)/day for 6 days. Determinations of cytochrome P450 (CYP) enzyme activities were carried out in hepatic microsomes isolated from rats treated. The activities of CYP2E1, CYP1A1/2 CYP2B1/2 and CYP4A1/2 enzymes significantly decreased after treatment with 1, 3 and 10 mg/kg bw/day, in a dose-dependent manner as compared to control. This effect was not observed after natamycin treatment at dose of 0.3 mg/kg bw/day. Our results suggest that natamycin may not potentiate the toxicity of many xenobiotics via metabolic activation and/or accumulation of reactive metabolites but also might affect the clearance of other xenobiotics detoxified by the studied CYP enzymes.     

Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-690514, a Potent Inhibitor of EGFR and VEGFR2

BMS-690514, a potent inhibitor of human epidermal growth factor receptor (HER) 1 (EGFR), 2, and 4, and vascular endothelial growth factor receptors (VEGFR) 1–3, is currently under investigation as an oral agent for the treatment of solid tumors. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism. Through integration of in vitro and in vivo pharmacokinetic data and antitumor efficacy in nude mice, human pharmacokinetics and efficacious doses were projected for BMS-690514. The oral bioavailability of BMS-690514 was 78% in mice, ~ 100% in rats, 8% in monkeys, and 29% in dogs. The low oral bioavailability in monkeys could be attributed to high systemic clearance in that species, which was also consistent with predicted clearance using in vitro data from monkey liver microsomes. Permeability of BMS-690514 in Caco-2 cells was in the intermediate range with a moderate potential to be a P-gp substrate. Experiments using recombinant human CYP enzymes and human liver microsomes suggested that CYP2D6 and CYP3A4 are likely to play a key role in the metabolic clearance of BMS-690514; in addition, direct glucuronidation of BMS-690514 was also observed in human hepatocytes. BMS-690514 was able to cross the blood-brain barrier with a brain-to-plasma ratio of ~ 1. The preclinical ADME properties of BMS-690514 suggest good oral bioavailability in humans and metabolism by multiple pathways including oxidation and glucuronidation. Based on the efficacious AUC in nude mice and predicted human pharmacokinetics, the human efficacious QD dose is predicted to be in the range of 100-200 mg.     

Toxic effects of dietary exposure to T-2 toxin on intestinal and hepatic biotransformation enzymes and drug transporter systems in broiler chickens

The effects of the mycotoxin T-2 on hepatic and intestinal drug-metabolizing enzymes (cytochrome P450) and drug transporter systems (MDR1 and MRP2) in poultry were investigated during this study. Broiler chickens received either uncontaminated feed, feed contaminated with 68 μg/kg or 752 μg/kg T-2 toxin. After 3 weeks, the animals were euthanized and MDR1, MRP2, CYP1A4, CYP1A5 and CYP3A37 mRNA expression were analyzed using qRT-PCR. Along the entire length of the small intestine no significant differences were observed. In the liver, genes coding for CYP1A4, CYP1A5 and CYP3A37 were significantly down-regulated in the group exposed to 752 μg/kg T-2. For CYP1A4, even a contamination level of 68 μg/kg T-2 caused a significant decrease in mRNA expression. Expression of MDR1 was not significantly decreased in the liver. In contrast, hepatic MRP2 expression was significantly down-regulated after exposure to 752 μg/kg T-2. Hepatic and intestinal microsomes were prepared to test the enzymatic activity of CYP3A. In the ileum and liver CYP3A activity was significantly increased in the group receiving 752 μg/kg T-2 compared to the control group. The results of this study show that drug metabolizing enzymes and drug transporter mechanisms can be influenced due to prolonged exposure to relevant doses of T-2.     

An antioxidant,N,N′-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: A 28-day repeated dose test and reproduction/developmental toxicity test

A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N′-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42–46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively.     

Effects of rifampin on CYP2E1-dependent hepatotoxicity of isoniazid in rats

Isoniazid and rifampin are first line drugs used to prevent and treat tuberculosis. The effects of rifampin co-administration on isoniazid-induced oxidative stress were investigated by the determination of the changes in hepatic metabolizing enzymes and DNA damage. Rats were treated with isoniazid alone (100 mg/kg, i.p.) or co-treated with rifampin (100 mg/kg, i.g.) for 10 or 21 days. Activities of CYP2E1, CYP1A1, CYP3A and glutathione S-transferases (GSTs) were analyzed by specific substrates. DNA oxidative damage by drug treatments was analyzed in precision-cut liver slices by HPLC–MS/MS. Isoniazid significantly increased CYP2E1 activities above control levels after 10 or 21 days treatment (2.25–4.59-fold), indicated by both chlorzoxazone hydroxylase and aniline hydroxylase (p < 0.01). Isoniazid treatment decreased activities of cytosolic total GST, alpha GST and mu GST after 21 days (p < 0.01). No change in activities of CYP1A1, CYP3A, and CYP3A1 mRNA expression was observed after isoniazid treatment. Rifampin co-administration significantly attenuated isoniazid-induced CYP2E1 levels (p < 0.01) and inhibition of mu GST (p < 0.01). Rifampin did not increase the formation of DNA adducts induced by isoniazid. These results suggest that rifampin co-administration does not increase isoniazid-induced oxidative stress through hepatic CYP2E1 during short-term treatment in experimental rats.     

Similarities in lindane induced alteration in cytochrome P450s and associated signaling events in peripheral blood lymphocytes and brain

Studies were initiated to investigate the similarities in alterations in cytochrome P450s (CYPs) and associated signaling events in brain and peripheral blood lymphocytes (PBL) induced by lindane, an organochlorine pesticide. Adult male albino wistar rats were treated orally with different doses (2.5- or 5.0- or 10- or 15 mg/kg/body weight) of lindane daily for 4 days. In another experiment, the treatment of low dose (2.5 mg/kg) of lindane was continued for 15- and 21 days. A dose- and time-dependent increase was observed in the activity of CYP dependent enzymes in brain microsomes and PBL isolated from the treated rats. However, the magnitude of induction was several folds less in PBL. As observed in brain, RT-PCR and Western immunoblotting demonstrated that increase in CYP enzymes in PBL is due to the increase in the mRNA expression of specific CYP isoenzymes. Similarities were also observed in activation of ERK and JNK MAP kinases and c-jun in PBL or brain isolated from rats treated with lindane. Similarities in the induction of CYPs and activation of MAP kinases in PBL and brain suggest that CYP expression profiles in PBL could be used for monitoring the exposure and toxicity of environmental chemicals.     

Transport of 5,5-diphenylbarbituric acid and its precursors and their effect on P-gp,MRP2 and CYP3A4 in Caco-2 and LS180 cells

AimTo examine the transport of 5,5-diphenylbarbituric acid sodium (T2007) and its mono- (MMMDPB) and di- (T2000) methoxymethylated precursors and their inducibility potential in Caco-2 and LS180 cells.MethodsTransport studies of T2000, MMMDPB and T2007 in Caco-2 cells were performed in Transwells. P-gp and CYP3A4 activities were assayed by [³H]digoxin and rhodamine 123 cellular retention and testosterone 6β-hydroxylation, respectively. Expressions of PXR, VDR and CAR mRNA and CYP3A4, MDR1/P-gp and MRP2 mRNA and protein were determined by qPCR and Western blotting, respectively. PXR siRNA was used to assess the involvement of PXR.ResultsThe P_app(A→B)s and P_app(B→A)s of T2000, MMMDPB and T2007 were similar (30–35 × 10^?6 cm/s) in Caco-2 cells. Treatment for 3 days with T2000 (15 μM), MMMDPB (70 μM) and T2007 (300 μM) generally furnished a greater induction in LS180 cells over the Caco-2 cells due to the higher, natural abundance of PXR. Changes in expression were confined mostly to MDR1 and CYP3A4: in LS180 cells, treatment for 3 days increased MDR1 and CYP3A4 but not MRP2 mRNA, and elevated P-gp and CYP3A4 protein expression that led to decreased cellular accumulation of [³H]digoxin and rhodamine 123, and enhanced testosterone 6β-hydroxylase activity towards T2007, respectively. The silencing of PXR by PXR siRNA in LS180 cells significantly attenuated the induction of MDR1 and CYP3A4.ConclusionsT2000, MMMDPB, and T2007 exhibited high permeabilities but are not P-gp substrates. T2007 and its analogs upregulated CYP3A4 and MDR1 modestly via the PXR.     

Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver

BackgroundRat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate of testosterone 2α- and 16α-hydroxylation.MethodsThe reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazodone – 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day), in the absence of antidepressants in vitro.ResultsThe investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on CYP2C11 activity, which were moderate (sertraline, nefazodone and clomipramine: K_i = 39, 56 and 66 μM, respectively), modest (fluoxetine and amitriptyline: K_i = 98 and 108 μM, respectively) or weak (imipramine and desipramine: K_i = 191 and 212 μM, respectively). Mirtazapine had no inhibitory effect on CYP2C11 activity. One-day exposure of rats to the antidepressant drugs did not significantly change the activity of CYP2C11 in liver microsomes; however, imipramine, desipramine and fluoxetine showed a tendency to diminish the activity of CYP2C11. Of the antidepressants studied, only desipramine and fluoxetine administered chronically elevated CYP2C11 activity; those effects were positively correlated with the observed increases in the enzyme protein level.ConclusionThree different mechanisms of the antidepressants-CYP2C11 interaction are postulated: 1) a direct inhibition of CYP2C11 shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo inhibition of CYP2C11 produced by one-day treatment with imipramine, desipramine and fluoxetine, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction of CYP2C11 produced by chronic treatment with desipramine and fluoxetine, which suggests their influence on enzyme regulation.     

The effects of acute pharmacological stimulation of the 5-HT,NA and DA systems on the cognitive judgement bias of rats in the ambiguous-cue interpretation paradigm

In the present study, we investigated the effects of acute pharmacological stimulation of the serotonergic (5-HT), noradrenergic (NA) and dopaminergic (DA) systems on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single injections of citalopram, desipramine or d-amphetamine and were subsequently tested with the ACI paradigm. Each drug was administered in 3 doses using a fully randomised Latin square design. Citalopram at the dose of 1 mg/kg significantly biased animals towards positive interpretation of the ambiguous cue, while at higher doses (5 and 10 mg/kg), the animals interpreted the ambiguous cue more negatively. Desipramine at all 3 tested doses (1, 2 and 5 mg/kg) significantly biased animals towards negative interpretation of the ambiguous cue, while d-amphetamine at the dose of 1 mg/kg induced positive bias, having no effects at lower doses (0.1 and 0.5 mg/kg). Our results indicate that cognitive bias in rats can be influenced by acute pharmacological intervention.     

Protective effects of carnosine alone and together with alpha-tocopherol on lipopolysaccharide (LPS) plus ethanol-induced liver injury

The aim of this study was to investigate the effect of carnosine (CAR) alone and together with vitamin E (Vit E) on alcoholic steatohepatitis (ASH) in rats. ASH was induced by ethanol (3 times; 5 g/kg; 12 h intervals, via gavage), followed by a single dose of lipopolysaccharide (LPS; 10 mg/kg; i.p.). CAR (250 mg/kg; i.p.) and Vit E (200 mg d-α-tocopherol/kg; via gavage) were administered 30 min before and 90 min after the LPS injection. CAR treatment lowered high serum transaminase activities together with hepatic histopathologic improvements in rats with ASH. Reactive oxygen species formation, malondialdehyde levels, myeloperoxidase activities and transforming growth factor β1 (TGF-β1) and collagen 1α1 (COL1A1) expressions were observed to decrease. These improvements were more remarkable in CAR plus Vit E-treated rats. Our results indicate that CAR may be effective in suppressing proinflammatory, prooxidant, and profibrotic factors in the liver of rats with ASH.     

Formulation Optimization and Bioavailability After Oral and Nasal Administration in Rabbits of Puerarin-Loaded Microemulsion

The main objective of the study was to investigate the efficacy of microemulsion (ME) to facilitate bioavailability of puerarin (PUE) after oral and nasal administration. The pseudo-ternary phase diagrams were constructed to screen the ME components and optimize the ME formulation. The optimized formulation for bioavailability assessment consisted of 20% Tween 80, 20% glycerin, and 1.6% ethyl oleate. The solubility (27.8 mg/mL) of PUE in ME was significantly improved compared to that (4.58 mg/mL) of crude PUE in water. The ME droplets were spherical with a mean particle diameter of 23.4 nm. After nasal (5 mg/kg) and oral (20 mg/kg) administration of a single dose of PUE as ME to fasted rabbits, the absolute bioavailability was 34.58% and 13.54%, respectively. It showed a shorter T_max (0.75 h) for nasal administration than that (1.0 h) for oral administration of PUE-loaded ME. The C_max of PUE-loaded ME was 0.55 μg/mL after nasal administration and 0.64 μg/mL after oral administration, respectively. The results showed that nasal administration might be a promising route to enhance the absorption of PUE in the form of ME.     

Pharmacokinetics,pharmacodynamics and toxicity of a combination of metoprolol succinate and telmisartan in Wistar albino rats: Safety profiling

Metoprolol succinate (MET), a cardioselective β blocker and telmisartan (TEL), an angiotensin receptor blocker were administered orally, both individually and in combination to Wistar albino rats for evaluation of their pharmacokinetics, pharmacodynamics and repeated dose oral toxicity (28 days). Pharmacokinetic study was performed by analyzing drug concentration in plasma by a developed and validated LC–MS/MS method following oral administration of MET and TEL at 2.5 mg/kg and 2.0 mg/kg dose, respectively, both individually and in combination. Antihypertensive activity of MET and TEL in above dose and manner was evaluated on artificially induced hypertension on laboratory animals. In repeated dose oral toxicity study, MET (60, 120 and 240 mg/kg/day) and/or TEL (12, 24 and 48 mg/kg/day) were administered to animals for 28 days followed by a recovery period of 14 days. Pharmacokinetic data revealed the probable absence of any pharmacokinetic interaction when co-administered. Improved blood pressure lowering effect was observed by combination therapy. Moreover, toxic effects obtained at high dose level of each treatment groups were transient and reversible and no evidence of additive toxic effects were observed due to concomitant administration. So, this combination can primarily be stated as safe which will be confirmed after clinical interaction studies in humans.     

Ninety day repeated gavage administration of Hipphophae rhamnoides extract in rats

Hippophae rhamnoides, is a high altitude plant, possesses immunomodulatory, anti-oxidant, anti-bacterial and adaptogenic activity and is widely used in treatment of various diseases. The present study was designed to ascertain the safety of aqueous extract of H. rhamnoides fruit when administered by gavage to rats for 90 days. Four groups of animals, each consisting of 15 males and 15 females, were adminstered 0, 100, 250, or 500 mg/kg extract, in a single dose/day. There were no treatment related change in mean body weight, organ/body weight ratio, histological, hematological and biochemical parameters studied in rats of either sex administered with extract at any dose evaluated. However, a significant increase in plasma glucose levels was observed in animals supplemented with 250 or 500 mg/kg extract, which returned to normal after a 2-week withdrawal of treatment. These results indicate no adverse effects of extract at a dose of 100 mg/kg body weight/day in rats administered for 90-days. Based on the findings of this study, the NOAEL was 100 mg/kg body weight/day of aqueous fruit extract of seabuckthorn in rats.