High blood pressure enhances brain stem neuronal nitric oxide synthase activity in Dahl salt‐sensitive rats

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Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG‐nitro‐l‐arginine methyl ester rat model of secondary hypertension

Objectives The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N^G‐nitro‐l ‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling. Methods Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L‐NAME rats received L‐NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK‐PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. Key findings A dose‐dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S‐carvedilol as compared with the R‐enantiomer was found in both experimental groups. Although the PK‐PD properties of the S‐carvedilol chronotropic effect were not altered in L‐NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L‐NAME rats. Conclusions Carvedilol showed enantioselective non‐linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L‐NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.     

Synergistic effect of spexin and progesterone on pain sensitivity attenuation in ovariectomized rats

Spexin is a central modulator of nociception. The aim of the present study was to investigate the effect of intra‐hippocampal CA3 (IHCA3) injection of spexin and spexin‐progesterone co‐administration on pain sensitivity in ovariectomized rat. Thirty‐five adult female rats were divided into five groups. Sham: the animals received injection of 0.5 μL ACSF by IHCA3. Experiments 1 and 2: the animals received injection of 0.5 μL of spexin bilaterally (10 and 30 nmol/rat respectively). Experiments 3 and 4: the animals received injection of 0.5 μL of spexin bilaterally (10 and 30 nmol/rat respectively) + subcutaneous (s.c.) injection of progesterone (5 mg/kg). Ovariectomy was performed in all groups to eliminate the effects of cyclic changes in the female rats. The formalin test (formalin 2.5%) was performed following the administration of spexin and progesterone. Results showed that bilateral injection of spexin in IHCA3 at both concentrations a significant (P < .05) decrease in the pain sensitivity in the two phases of formalin test. Similarly, the bilateral injection of spexin in IHCA3 at both concentrations following the s.c. injection of progesterone significantly (P < .05) decreases pain sensitivity in two phases of the formalin test. This pain attenuation due to the co‐administration of spexin and progesterone was more potent than spexin‐induced analgesia. According to the present results, spexin has a modulatory effect on pain sensitivity, which becomes more pronounced by progesterone administration.     

Surgery‐induced changes in rat IL‐1β and acetylcholine metabolism: role of physostigmine

Pharmacological enhancement of cholinergic activity following administration of physostigmine is known to induce protective effects generally. However, it is unclear whether the effect of physostigmine on inflammation and acetylcholine (ACh) metabolism is related to different types of surgical intervention or anaesthesia alone. To investigate this, rats were subjected to partial liver resection (PLR) or sham surgery, with a control group receiving anaesthesia alone. Half of each treatment group received a single intra‐operative dose of physostigmine (0.04 mg/kg); the others received placebo. Acetylcholinesterase (AChE) activity and plasma and brain concentrations of interleukin (IL)‐1β and ACh were determined. Both PLR and sham operation induced a time‐dependent increase in plasma concentrations of IL‐1β compared with rats receiving anaesthesia alone (3.9‐ and 4.8‐fold increases, respectively). In the brain, IL‐1β concentrations had increased approximately twofold after surgery compared with the control group. Blood AChE was transiently decreased after surgery. Brain AChE activity increased 1.3‐fold (P = 0.014) only after PLR; consequently, cerebral ACh concentrations were significantly reduced. Physostigmine administration significantly reduced IL‐1β and AChE levels. Cerebral ACh concentrations were markedly increased from 544 ± 122 ng/mg protein following placebo administration to 654 ± 93 ng/mg protein after physostigmine administrations (P < 0.001). We conclude that a single dose of physostigmine intra‐operatively has a sustained anti‐inflammatory effect (up to 120 min after injection) that is especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts a neuroprotective action by increasing levels of the neurotransmitter ACh.     

Anticancer activity using positron emission tomography‐computed tomography and pharmacokinetics of β‐eudesmol in human cholangiocarcinoma xenografted nude mouse model

Cholangiocarcinoma (CCA) is an important public health problem in several parts of South East Asia, particularly in Thailand. The limited availability of effective diagnostic tools for early stage CCA, including chemotherapeutic options, constitutes a major problem for treatment and control of CCA. The aim of the present study was to assess the anti‐CCA activity and pharmacokinetics of β‐eudesmol in CCA‐xenografted nude mouse model and healthy mice. Positron emission tomography‐computed tomography (PET‐CT) with ¹⁸F‐fluorodeoxyglucose was used for detecting and monitoring tumour development, and PET‐CT with technetium‐99m was used to investigate its pharmacokinetics property. Results support the role of PET‐CT as a potential tool for detecting and monitoring the progress of lung metastasis. Tumour size and lung metastasis were significantly inhibited by 91.6% (of baseline) and 95% (of total lung mass), respectively, following treatment with high‐dose β‐eudesmol (100 mg/kg body weight for 30 days). Survival time was prolonged by 64.4% compared with untreated controls. Systemic clearance of the compound was rapid, particularly during the first 60 min. The compound was distributed to the vital organs at maximum levels 2 h after oral administration and 15 min after intravenous injection. Results from the present study suggest the potential of β‐eudesmol as a promising candidate for further development as an anti‐CCA drug with respect to its pharmacodynamics and pharmacokinetic properties. PET‐CT, with radiotracers ¹⁸F‐fluorodeoxyglucose and technetium‐99m, was shown to be a reliable tool in the investigation of anti‐CCA and pharmacokinetic properties of β‐eudesmol in CCA‐xenografted and healthy mice.     

Physiological mechanisms for the increase in renal solute‐free water clearance by a glucagon‐like peptide‐1 mimetic

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Toxic effects of methamidophos on paraoxonase 1 activity and on rat kidney and liver and ameliorating effects of alpha‐tocopherol

The role of alpha‐tocopherol on nephrotoxicity and hepatotoxicity induced by methamidophos (MT) was investigated in wistar rats. Animals were given via gavage, for four weeks, a low dose of MT (MT1), a high dose of MT (MT2), vitamin E (200 mg/kg of bw) or both MT2 plus vitamin E (Vit E) and control group was given distillate water. MT treatment resulted in a significant decrease in the body weight of MT2‐treated group. Moreover, MT‐treated groups had significantly lower butyrylcholinesterase (p < 0.01) and paraoxonase 1 (PON1) activities compared with the control group (p < 0.05). However, MT2‐treated group had significantly higher alkaline phosphatase activity compared with untreated rats (p < 0.05). Both MT‐treated groups had significantly higher urea (p < 0.01) and uric acid levels (p < 0.05) compared with the control group. However, significant low uric acid level (p < 0.05) was noted in MT2 plus vit E‐treated rats compared with MT2‐treated group. Histopathological changes in organ tissues were observed in both MT‐treated groups and MT2 plus vit E‐treated rats. However, the damage was reduced in MT2 plus vit E‐treated rats. Therefore, this study deduces that alpha‐tocopherol administration may ameliorate the adverse effects of subacute exposure to MT on rat liver and kidney and this antioxidant can protect PON1 from oxidative stress induced by this organophosphorus pesticide. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 842–854, 2016.     

Determination of pharmacokinetic parameters of vitamin K1 in rats after an intravenous infusion

Pharmacokinetic parameters of vitamin K1 have a large range of values in different literature. The aim of this study was to determine the pharmacokinetic parameters of vitamin K1 following post-constant speed intravenous infusion (PCSII) to provide rational pharmacokinetic parameters of vitamin K1 and compare these with results of noncompartmental analysis following intravenous injection (IV). After 15 hours intravenous infusion of vitamin K1 in rats, the logarithmic concentration–time curve of vitamin K1 was fit to a linear equation following PCSII (R² = 0.9599 ± 0.0096). Then, half-time (T_1/2), apparent volume of distribution (V_d), and clearance rate (CL) were estimated successively. T_1/2 of vitamin K1 was 4.07 ± 0.41 hour, CL was 89.47 ± 3.60 mL/h, and V_d was 525.38 ± 54.45 mL in rats following PCSII. There was no significant difference in pharmacokinetic parameters of vitamin K1 among different sampling times. For noncompartmental analysis, T_1/2 and mean residence time (MRT_INF) for a sampling duration of 6h were shorter than those of 12 hours or 24 hours sampling duration following IV (P < .05, P < .01). In addition, T_1/2 of vitamin K1 was obviously different from MRT-equated half-time (T_{1/2, MRT})(P < .05). V_d and CL of vitamin K1 following PCSII were larger than those following IV based on noncompartmental analysis (P < .01). The results demonstrated that drug distribution in the body was balanced and the Napierian logarithmic concentration–time curve of vitamin K1 fit to a linear equation following PCSII. Vitamin K1 has a long T_1/2 and a relatively large V_d following PCSII.     

Effect of inflammatory factor‐induced cyclo‐oxygenase expression on the development of reperfusion‐related no‐reflow phenomenon in acute myocardial infarction

No reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. Increased levels of inflammatory factors, including C‐reactive protein (CRP), in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) may affect myocardial perfusion. However, why the no‐reflow phenomenon increases in inflammation stress after PCI is not clear. The aim of the present study was to determine the effects and molecular mechanisms underlying the effects of CRP on the expression of cyclo‐oxygenase (COX) on the development of the no‐reflow phenomenon. There was a significant increase in plasma levels of CRP and interleukin (IL)‐6 in no‐reflow patients, suggesting that inflammatory factors play an important role in the development of the no‐reflow phenomenon. The mechanisms involved were further evaluated after reperfusion in a rat model mimicking the no‐reflow phenomenon. Compared with normal reflow rats, there were significant increases in both COX‐1 and COX‐2 in cardiac tissue from no‐reflow rats. The COX inhibitor indomethacin (5 mg/kg, i.p.) significantly reduced the no‐reflow area. In another series of experiments, human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations (5–25 μg/mL). C‐Reactive protein significantly increased COX‐1 and COX‐2 levels in a time‐ and concentration‐dependent manner. In addition, extracellular signal‐regulated kinase (ERK) and Jun N‐terminal kinase (JNK) were activated in CRP (5, 10, 25 μg/mL)‐treated HCAEC cultures. Furthermore, the ERK inhibitor pd98059 (30 μmol/L) and the JNK inhibitor sp600125 (10 μmol/L) blocked CRP‐induced COX‐1 and COX‐2 expression for 12 h. Together, the findings of the present study suggest that CRP can promote the development of the no‐reflow phenomenon by increasing COX‐1 and COX‐2 expression, which is regulated, in part, via ERK and JNK activity.     

Population pharmacokinetic‐pharmacodynamic modelling of liquid and controlled‐release formulations of oxycodone in healthy volunteers

Oral controlled‐release formulations are playing an ever‐increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic‐pharmacodynamics of two controlled‐release tablet formulations and a liquid formulation of oxycodone in healthy, opioid‐naïve volunteers, which can serve as a reference for future patient studies. A semi‐double‐blinded, three‐way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled‐release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre‐dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post‐dose. Oxycodone pharmacokinetics was best described by a two‐compartment model with first‐order absorption. The controlled‐release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k_aCR = 0.19 hour^‐1) compared to the oral solution (k_aSOL = 0.94 hour^‐1). Effects on pupil diameter were delayed relative to plasma (14 minutes half‐life) for all formulations and were best described by a proportional E_max model. The plasma concentration of oxycodone at half‐maximum effect was lower in males (31.1 μg/L) compared to females (52.8 μg/L; P < .001). The absorption profile of controlled‐release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled‐release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.     

Role of peripheral purinoceptors in the development of bee venom‐induced nociception: A behavioural and electrophysiological study in rats

Colocalization of purinergic P2X and P2Y receptors in dorsal root ganglion sensory neurons implies that these receptors play an integrative role in the nociceptive transmission process under inflammatory conditions. In the present study, behavioural and in vivo electrophysiological methods were used to examine the peripheral role of P2 receptors in the persistent nociceptive responses induced by subcutaneous bee venom injection (2 mg/mL) in. Sprague‐Dawley rats Local pretreatment with the wide‐spectrum P2 receptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS; 1 mmol/L, 50 μL) 10 min prior to s.c. bee venom injection significantly suppressed the duration of spontaneous nociceptive lifting/licking behaviour, inhibited mechanical hyperalgesia and decreased the firing of spinal dorsal horn wide dynamic range neurons in response to bee venom, without affecting primary thermal and mirror‐image hyperalgesia. The localized antinociceptive action of PPADS was not due to a systemic effect, because application of the same dose of PPADS to the contralateral side was not effective. The results suggest that activation of peripheral P2 receptors is involved in the induction of nociceptive responses, mechanical hyperalgesia and the excitation of sensory spinal neurons.     

Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP‐C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry

A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6–200 µg/L, intra‐day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti‐cancer drug BP‐С1, a complex of cis‐configured platinum and benzene‐poly‐carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half‐life times for α‐ and β‐phase) were estimated for two dosage forms of BP‐C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP‐C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days’ break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. ‘Slow’ phase of platinum excretion kinetics may be related to the muscles at the injection site. © 2015 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.     

Different mechanisms of acute versus long‐term antihypertensive effects of soluble epoxide hydrolase inhibition: Studies in Cyp1a1‐Ren‐2 transgenic rats

Recent studies have shown that the long‐term antihypertensive action of soluble epoxide hydrolase inhibition (sEH) in angiotensin‐II (AngII)‐dependent hypertension might be mediated by the suppression of intrarenal AngII levels. To test this hypothesis, we examined the effects of acute (2 days) and chronic (14 days) sEH inhibition on blood pressure (BP) in transgenic rats with inducible AngII‐dependent hypertension. AngII‐dependent malignant hypertension was induced by 10 days’ dietary administration of indole‐3‐carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1‐Ren‐2 transgenic rats. BP was monitored by radiotelemetry. Acute and chronic sEH inhibition was achieved using cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid, given at doses of 0.3, 3, 13, 26, 60 and 130 mg/L in drinking water. At the end of experiments, renal concentrations of epoxyeicosatrienoic acids, their inactive metabolites dihydroxyeicosatrienoic acids and AngII were measured. Acute BP‐lowering effects of sEH inhibition in I3C‐induced rats was associated with a marked increase in renal epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids ratio and acute natriuresis. Chronic treatment with cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced rats elicited dose‐dependent persistent BP lowering associated with a significant reduction of plasma and kidney AngII levels. Our findings show that the acute BP‐lowering effect of sEH inhibition in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated by a substantial increase in intrarenal epoxyeicosatrienoic acids and their natriuretic action without altering intrarenal renin–angiotensin system activity. Long‐term antihypertensive action of cis‐4‐(4‐(3‐adamantan‐1‐yl‐ureido)cyclohexyloxy) benzoic acid in I3C‐induced Cyp1a1‐Ren‐2 transgenic rats is mediated mostly by suppression of intrarenal AngII concentration.     

Antihypertensive and vascular remodelling effects of the imperatorin derivative OW1 in renovascular hypertension rats

OW1 is a novel imperatorin derivative that exhibits vasodilator activity. In the present study, the antihypertensive effect of and inhibition of vascular remodelling by OW1 were investigated in two‐kidney, one‐clip (2K1C) renovascular hypertensive rats. Rats were subjected to the 2K1C procedure and treated with OW1 (40 or 80 mg/kg per day) for 8 weeks. Blood pressure was measured in conscious rats. Microalbumin (mALB) and total protein (U‐TP) concentrations were determined in the urine, as were plasma concentrations of angiotensin (Ang) II, calcitonin gene‐related peptide (CGRP) and angiotensin‐converting enzyme 1 (ACE). The unclipped kidney was stained with haematoxylin and eosin and Masson trichrome, whereas aortic sections were stained with Masson trichrome. In addition, OW1‐induced vasodilatation was evaluated in vitro in rat mesenteric and renal arteries. Immunohistochemical analysis was used to quantify collagen I and III expression. OW1 relaxed rat mesenteric and renal arterial rings in vitro. Treatment of 2K1C hypertensive rats with OW1 (40 and 80 mg/kg per day) for 8 weeks significantly decreased blood pressure. In addition, OW1 reduced plasma AngII and ACE concentrations and increased plasma CGRP concentrations. At 80 mg/kg per day, OW1 decreased blood urea nitrogen, mALB and U‐TP levels. Histological analysis revealed that OW1 reduced renal arteriolar thickness and relieved the structural hypertrophic arteries. Moreover, OW1 had an inhibitory effect on vascular remodelling and renal lesions in hypertensive rats. In conclusion, the results suggest that OW1 could potentially be a novel candidate for hypertension intervention.     

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high‐cholesterol‐fed rats. Male Sprague‐Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high‐cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high‐cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine‐treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine‐conjugated bile acids by 61% and decreased glycine‐conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine‐conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α‐hydroxylase (CYP7A1), the rate‐limiting enzyme for bile acid synthesis, by three‐ and two‐fold, respectively. Taurine also decreased the enzymatic activity of acyl‐CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine‐conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.     

Nitric oxide signalling is involved in diarylheptanoid‐induced increases in femoral arterial blood flow in ovariectomized rats

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Antioxidant effect of atorvastatin is independent of PON1 gene T(–107)C,Q192R and L55M polymorphisms in hypercholesterolaemic patients

ABSTRACT

Background: Serum paraoxonase (PON1), a high density lipoprotein (HDL)-bound antioxidant enzyme, plays a role in atherosclerosis. An increase in PON1 activity has been reported following statin treatment.

Objective: In the present study the following factors were evaluated: the influence of PON1 gene Q192R, L55M and T(–107)C polymorphisms on the response of LDL oxidisability and PON1 activity to atorvastatin treatment.

Research design and methods: 205 Sicilian subjects with primary hypercholesterolaemia (HCh) and 69 healthy subjects as controls were concurrently enrolled. Hypercholesterolaemic patients were randomly divided into two groups: an atorvastatin group (10?mg/day atorvastatin) and a placebo group. Lipid profile, markers of LDL resistance to in vitro oxidation (lag-phase, oxidation rate and thiobarbituric acid-reactive substances), vitamin E content in LDL, PON1 activity and genotypes in both HCh and control subjects were determined at baseline. The same parameters were measured again after 3 weeks of treatment in both the atorvastatin and placebo groups.

Results: HCh subjects showed significantly lower LDL resistance to oxidation, vitamin E content and PON1 activity levels than controls. A strong association was found among PON1 T(–107)C genotypes, LDL susceptibility to oxidation, vitamin E content and PON1 activity. After treatment, the atorvastatin group displayed a significant decrease in total cholesterol, LDL-cholesterol levels, and LDL susceptibility to oxidation, and an increase in vitamin E content and PON1 activity, compared with baseline values. Unlike PON1 activity levels, no difference among PON1 gene polymorphisms and reduction in markers of LDL oxidisability was observed.

Conclusions: These results show, for the first time, that atorvastatin is able to improve the resistance to LDL oxidation independently of PON1 gene polymorphism.     

Effects of myricetin,an antioxidant,on the pharmacokinetics of losartan and its active metabolite,EXP‐3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P‐glycoprotein inhibition by myricetin

Objectives The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP‐3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P‐glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases. Methods The pharmacokinetic parameters of losartan and EXP‐3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P‐glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated. Key findings Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 µm , respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF‐7/ADR cells overexpressing P‐glycoprotein in a concentration‐dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration–time curve of losartan by 31.4–61.1% and peak plasma concentration of losartan by 31.8–50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half‐life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite–parent area under the plasma concentration–time curve ratio by 20%, implying that myricetin may inhibit the CYP‐mediated metabolism of losartan to its active metabolite, EXP‐3174. Conclusions The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4‐ and CYP2C9‐mediated metabolism of losartan in the small intestine or in the liver, and the P‐glycoprotein efflux pump in the small intestine by myricetin.     

An improved radiosynthesis of O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate: A first‐in‐class cholinesterase PET tracer

O‐(2‐Fluoroethyl)‐O‐(p‐nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl‐serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo . The corresponding radiolabeled O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl) methylphosphonate, [ ¹⁸ F]1 , has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [ ¹⁸ F]1 tracer synthesis was slow even with microwave acceleration, required high‐performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis‐(O,O‐p‐nitrophenyl) methylphosphonate, 2 , with 2‐fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [ ¹⁸ F]1 , was obtained in a non‐decay–corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [ ¹⁸ F]1 , which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo .     

Amorphous solid dispersions of carvedilol along with pH‐modifiers improved pharmacokinetic properties under hypochlorhydoria

Carvedilol (CAR) belongs to biopharmaceutics classification system class‐II drugs, with poor aqueous solubility and pH‐dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR‐ASD was prepared by freeze‐drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole‐treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH‐modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR‐ASD formulation with 50% loading of CA (CAR‐ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally‐dosed CAR‐ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole‐treated rats. From these findings, addition of CA as pH‐modifier in CAR‐ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.