Assessment of drug-drug interaction of dapagliflozin with LCZ696 based on an LC-MS/MS method.

The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma.

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.

A Review of Hedgehog Inhibitors Sonidegib and Vismodegib for Treatment of Advanced Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between sonidegib and vismodegib is their respective pharmacokinetic profiles with sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Simultaneous determination of sacubitrilat and fimasartan in rat plasma by a triple quad liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive mode.

An LC-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of fimasartan and sacubitrilat using positive ion mode. The protein precipitation method was employed for the extraction of fimasartan, sacubitrilat and alprazolam (internal standard) from rat heparinized plasma. Baseline separation of the analytes was accomplished using an ACE-5, C18 (4.6 × 50 mm) column and gradient elution of mobile phase A (5 mm ammonium formate and 0.1% formic acid in purified water) and B (acetonitrile:methanol, 80:20; v/v). All peaks of interest were eluted within a 5-min runtime. The quantitation was achieved in the selected reaction monitoring mode. The developed method was validated as per US Food and Drug Administration guidelines and met the pre-defined acceptance criteria. The method showed linearity from 5 to 10,000 ng/mL. The accuracy/precision of intra- and inter-batch assays was 96.64%/2.05% to 109.17%/13.70% and 100.74%/3.76% to 106.39%/9.75% for fimasartan and 100.02%/1.49% to 113.80%/9.38% and 100.75%/2.31% to 108.40%/7.74% for sacubitrilat, respectively, in rat plasma. Fimasartan and sacubitrilat remained stable in rat plasma at different experimental conditions up to 21 days. The developed method was sensitive, selective and applied successfully to monitor plasma concentrations of fimasartan and sacubitrilat in an oral rat pharmacokinetic study.

Synergistic co-delivery of diacid metabolite of norcantharidin and ABT-737 based on folate-modified lipid bilayer-coated mesoporous silica nanoparticle against hepatic carcinoma.

Diacid metabolite as the stable form of norcantharidin (DM-NCTD) derived from Chinese blister beetle (Mylabris spp.). The previous studies reported that DM-NCTD could enhance ABT-737-triggered cell viability inhibition and apoptosis in hepatocellular carcinoma (HCC) cell lines. To translate this synergistic therapy into in vivo anticancer treatment, a folate receptor-targeted lipid bilayer-supported chlorodimethyloctadecylsilane-modified mesoporous silica nanoparticle (FA-LB-CHMSN) with DM-NCTD loaded in CHMSN and ABT-737 in lipid bilayer was prepared, which could promote the cancer cell uptake of the drugs through folate receptor-mediated endocytosis. The structure and the properties of the nanoparticle were evaluated. FA-LB-CHMSN with DM-NCTD/ABT-737 loaded induced apparent tumor cell apoptosis and showed remarkably tumor inhibition in H22 tumor-bearing mice model, with significant cellular apoptosis in the tumor and no obvious toxicity to the tissues. We expect that this nanoparticle could be of interest in both biomaterial investigations for HCC treatment and the combination of chemotherapeutic drugs for synergistic therapies.

A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor.

To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).

Simultaneous determination of TUG-891 and its metabolites in rat plasma using LC-HRMS with application to preclinical pharmacokinetic study.

In this study, a simple and reliable LC-MS/MS method was first proposed for the simultaneous determination of TUG-891 and its metabolites TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat plasma. The analytes and fasiglifam (internal standard) were extracted from plasma samples with acetonitrile and separated using an Acquity BEH C18 column (1.7 µm, 2.1 × 50 mm) with water containing 0.05% ammonium hydroxide and acetonitrile containing 0.05% ammonium hydroxide as the mobile phase. A Q-Exactive Orbitrap mass spectrometer in full-scan mode was used for mass detection, and the data analysis was obtained using a mass extraction window of 5 ppm. The calibration curves exhibited excellent linearity (correlation coefficient > 0.9981) in the concentration range of 0.5-1000 ng/mL. The lower limit of quantification was 0.5 ng/mL for all analytes. The intra- and inter-day precision was less than 11.31%, and the accuracy ranged from -11.50 to 9.50%. The extraction recovery of the analytes from rat plasma was greater than 82.31%, and no obvious matrix effect was found. The established method was further applied to the pharmacokinetic study of TUG-891, TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat after a single dose of 5-mg/kg treatment of TUG-891. The results demonstrated that TUG-891 was rapidly metabolized into its metabolites and the systemic exposures of the metabolites were much higher than those of TUG-891.

New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium.

Candesartan cilexetil (CC) is a poorly soluble antihypertensive drug with in vivo absorption limited by its low aqueous solubility. Aiming to generate CC supersaturation as strategy to improve its absorption and bioavailability, amorphous solid dispersions (ASDs) of CC with hydroxypropylmethylcellulose acetate succinate type M (HPMCAS M) were developed and evaluated by in vitro and in vivo techniques. The ASDs were characterized by several solid-state techniques and evaluated regarding the supersaturation generation and maintenance under non-sink conditions in biorelevant medium. Stability studies at different storage conditions and in vivo pharmacodynamics studies were performed for the best formulation. The ASD developed presented appropriate drug amorphization, confirmed by solid state characterization, and CC apparent solubility increases around 85 times when compared to the pure crystalline drug. Supersaturation was maintained for up to 24 h in biorelevant medium. The in vivo pharmacodynamics studies revealed that ASD of CC with the polymer HPMCAS M presented an onset of action about four times faster when compared to the pure crystalline drug. The CC-HPMCAS ASD were successfully developed and demonstrated good physical stability under different storage conditions as well as promising results that indicated the ASD potential for improvement of CC biopharmaceutical properties.

Dissipation pattern and residual levels of boscalid in cucumber and soil using liquid chromatography-tandem mass spectrometry.

To stipulate the rationale of spraying doses and to determine the safe interval period of boscalid suspension concentrate (SC), the degradation dynamics and residual levels were investigated in cucumber and soil using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Field trials were conducted according to Chinese Guideline on pesticide residue trials. Following application, the degradation kinetics was best ascribed to first-order kinetic models with half-life of 2.67-9.90 d in cucumber. Spraying boscalid SC at 1.5-fold the recommended dosage yield terminal residues, which are clearly lower than the maximum residue limit (MRL) established by China (MRL =5 mg.kg-1) in cucumber. At variance, the dissipation dynamics in soil did not fit to first-order kinetics and the half-life was more than 17 days, the finding which denotes that the degradation behavior of boscalid in soil proceeds slowly. It has therefore been shown that boscalid is safe for use on cucumbers under the recommended dosage.

Fimasartan reduces neointimal formation and inflammation after carotid arterial injury in apolipoprotein E knockout mice.

BACKGROUND: The beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on atherosclerosis have been demonstrated in numerous studies. We investigated the effects of fimasartan on reducing neointimal formation and systemic inflammation after carotid artery (CA) injury in Apolipoprotein E knockout (ApoE KO) mice. METHODS: ApoE KO mice were randomly allocated to Group I (without CA injury), Group II (without CA injury + Fimasartan), Group III (CA injury), and Group IV (CA injury + Fimasartan). Fimasartan was orally administered everyday starting 3 days before iatrogenic left CA injury. RESULTS: At 28 days, neointimal hyperplasia and the inflammatory cytokines including TNFα, IL-6, ICAM, and MMP-9 in the peripheral blood were significantly reduced in Groups II and IV compared to Groups I and III, respectively. All fimasartan-administered groups revealed significant increases of CD4+CD25+Foxp3+ regulatory T (Treg) cells with increased plasma levels of IL-10 and TGFß. In addition, increased CD8+ T cells by fimasartan were correlated with reduced smooth muscle cell (SMC) proliferation in the neointima in Groups II and IV. Furthermore, the populations of Treg and CD8+ T cells in total splenocytes were increased in Groups II and IV compared to Groups I and III, respectively. The enlargement of spleens due to CA injury in the Group III was attenuated by fimasartan, as shown in the Group IV. These data indicate that fimasartan significantly reduced SMC proliferation in neointima and increased Treg cells in ApoE KO CA injury mice. CONCLUSIONS: This study suggests fimasartan could be an efficient strategy for reduction of atherosclerotic progression, with a decrease in immune response and systemic inflammation.

Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans.

Exp3174 is an active metabolite of losartan for the treatment of hypertension. Allisartan (ALS3) is a marketed ester prodrug of Exp3174 to reduce bioavailability variation of losartan in China. However, ALS3 exhibited a lower oral absorption than losartan in humans. In this study, the enzymes and transporters involved in ALS3 and Exp3174 disposition were investigated to clarify the mechanisms. ALS3 underwent extensive hydrolysis to Exp3174 in S9 of Caco-2 cells, human intestine microsomes (HIM), recombinant carboxylesterase (rCES) 1, and rCES2. ALS3 exhibited similar affinity in HIM and rCES2 with K m values of 6.92 and 6.77 µM, respectively, indicating that ALS3 is mainly hydrolyzed to Exp3174 in human intestine by CES2. Transport assays of ALS3 and Exp3174 suggested that ALS3 and Exp3174 are substrates of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 2 with poor permeability. Organic anion-transporting polypeptide 2B1 showed higher affinity and clearance toward ALS3 (K m 0.75 µM and intrinsic clearance 215 µl/min/mg) than those of Exp3174 (K m 7.85 µM and intrinsic clearance 16.1 µl/min/mg), indicating that ALS3 is preferred to be uptaken into intestinal epithelia. Hydrolysis of ALS3 was increased from approximately 30% to 55% in CES2-transfected human embryonic kidney 293-OATP2B1 cells, indicating the possible interplay between OATP2B1 and CES2. The influx and efflux of ALS3 across Caco-2 cells increased the potential of ALS3 hydrolysis to Exp3174, and the produced Exp3174 was rapidly pumped out, which led to undetectable ALS3 and Exp3174 in basolateral (receiver) side in Caco-2 cells. Overall, our study provided supportive evidences that the interplay between CES2 and transporters in intestine contributes to the low bioavailability of ALS3 in humans.

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis.

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 µM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

In vitro metabolism of magnolol and honokiol in rat liver microsomes and their interactions with seven cytochrome P substrates.

RATIONALE: Magnolol and honokiol are the main active components of Magnolia officinalis Rehd. et Wils. The study of their interactions with liver microsomes is very important for the clinical safety of M. officinalis Rehd. et Wils. METHODS: The main metabolites of magnolol and honokiol in rat liver microsomes were investigated using ultrahigh-performance liquid chromatography/mass spectrometry and their possible structures were identified. In addition, cytochrome P450 (CYP450) isoenzymes of the major rat metabolites of magnolol and honokiol were identified using a specific inhibitor. RESULTS: This study suggests that the CYP2E1 subtype is responsible for the oxidation of magnolol and honokiol terminal double bonds to epoxy metabolites. CYP3A4 appears to be the major subtype responsible for further hydrolytic metabolism, while CYP1A2 may promote decarboxylation of the metabolites. CYP2A6 may be the main subtype responsible for the hydrogenation of magnolol (p < 0.05). CONCLUSIONS: This study demonstrated that different CYP450 enzyme isoforms showed different activities in the in vitro metabolism of magnolol and honokiol in rat liver microsomes. It has certain practical applications in that we should pay attention to drug-drug interactions in clinical medications and also to drug-enzyme interactions.

Evaluation of pharmacokinetic interactions between bicyclol and co-administered drugs in rat and human liver microsomes in vitro and in rats in vivo.

Bicyclol is a new synthetic anti-hepatitic drug and primarily metabolized by CYP3A. The aim of this study was to evaluate the pharmacokinetic interactions between bicyclol and co-administered drugs including metformin, pioglitazone, atorvastatin, fenofibrate, Cyclosporin A (CsA), and tacrolimus in rat and human liver microsomes (RLMs/HLMs) in vitro and in rats in vivo. The depletion rate of bicyclol in RLMs was significantly inhibited by 44.8% and 35.5% after preincubation with pioglitazone and fenofibrate while the metabolite formation rate of bicyclol in HLMs was inhibited by 26.1% and 23.9% after preincubation and coincubation with tacrolimus, and by 20.2% after preincubation with CsA. Conversely, preincubation and coincubation with bicyclol significantly inhibited the depletion rate of pioglitazone in RLMs by 34.1% and 27.1%, respectively, and the formation rate of para- and ortho-hydroxy atorvastatin in RLMs and HLMs by 20.6-36.2%. There were no significant pharmacokinetic interactions between bicyclol and pioglitazone in rats after a single or multiple oral treatment. As the selected inhibitory drug concentrations in vitro were significantly higher than those in clinical settings and the maximum inhibition rate did not exceed 50%, the clinically significant interaction between bicyclol and these co-administered drugs in humans is predicted less likely to happen.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

Pharmacokinetic analysis of plasma bicyclol by liquid chromatography-tandem mass spectrometry.

Bicyclol is a synthetic drug widely used to treat chronic hepatitis B. This study aimed to develop a selective, sensitive and high-throughput liquid chromatography-tandem mass spectrometric method for the detection of bicyclol in human plasma. Bicyclol was detected using a multiple reaction monitoring mode, with ammonium adduct ions (m/z 408.2) as the precursor ion and the [M-CH3 ]+ ion (m/z 373.1) subjected to demethylation as the product ion. Chromatographic separation was achieved using a Zobax Eclipse XDB-C18 column with a gradient elution and a mobile phase of 2 mm ammonium formate and acetonitrile. Bicyclol was extracted from plasma matrix by precipitation. A linear detection response was obtained for bicyclol ranging from 0.500 to 240 ng/mL, and the lower limit of quantification was 0.500 ng/mL. The intra- and inter-day precisions were all ≤7.4%, and the accuracies were within ±6.0%. The extraction recovery was >95.9%, and the matrix effects were between 96.0% and 108%. Bicyclol was found to be unstable in human plasma at room temperature, but the degradation was minimized by conducting sample collection and preparation in an ice bath. The validated method was successfully applied to investigate the pharmacokinetics of bicyclol tablets in six healthy Chinese volunteers.

Comparative pharmacokinetic study of four major bioactive components after oral administration of Zhi-Zi-Hou-Po decoction in normal and corticosterone-induced depressive rats.

A highly selective and efficient LC-MS/MS method was developed to determine the plasma concentration of magnolol, hesperidin, neohesperidin and geniposide following oral administration of Zhi-Zi-Hou-Po decoction in normal and depressed rats. Plasma samples were pretreated by protein precipitation with methanol. Chromatographic separation was performed on an XTerra® MS C18 column using a gradient elution with a mobile phase composed of acetonitrile-0.1% aqueous formic acid. The proposed method was validated to be specific, accurate and precise for the analytes determination in plasma samples. The calibration curves displayed good linearity over definite concentration ranges for the analytes. The intra- and inter-day precision of the proposed method at three different levels were all within <11.13% and the relative errors ranged from -8.46 to 8.93%. The recovery of the four compounds ranged from 82.72 to 89.08% and no apparent matrix effect was observed during sample analysis. After full validation, the established method was successfully applied for comparing the pharmacokinetics of four components between normal and depressed rats. The results showed that the AUC and Cmax of four analytes in depressed rats were significantly different from those in normal rats and might provide helpful information to guide the clinical use of Zhi-Zi-Hou-Po to treat depression.

Evaluation of gender difference in pharmacokinetics of Candesartan cilexetil in the fasted state by RP-HPLC: A single dose comparative study.

To compare the pharmacokinetics of candesartan cilexetil in healthy male and female volunteers in order to identify possible influence of gender and to improve therapeutic outcomes, an HPLC method for the quantification of candesartan cilexetil was developed and validated. Total of 16 volunteers (8 male and 8 female) were registered. Candesartan cilexetil 16 mg was administered orally to all the volunteers and blood samples were collected at different time intervals between 0-72 hours. Plasma was separated and analysed by HPLC method. Pharmacokinetic parameters were calculated by using APO software MW/PHARM version 3.02 and compared in male and female volunteers. The developed HPLC method fulfils the criteria for linearity, accuracy and precision described in EMA guideline. The values for absorption rate constant (Ka), maximum plasma concentration (Cmax), volume of distribution (Vd) and Clearance (CL) were similar in male and female volunteers. No influence of gender was observed on overall pharmacokinetics of candesartan cilexetil. Therefore, no need for dose optimization while administering candesartan cilexetil in male and female patients was found based on the results of this study.

Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease with a dismal prognosis and a largely unknown etiology. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for extracellular production of lysophosphatidic acid (LPA), a bioactive phospholipid. LPA has numerous effects in most cell types, signaling through at least 6 receptors (LPAR) exhibiting wide spread distribution and overlapping specificities. The ATX/LPA axis has been suggested as a therapeutic target in different chronic inflammatory and fibroproliferative disorders, including pulmonary fibrosis. In this report, we examined head-to-head the efficacy of a potent inhibitor of ATX (PF-8380), that has not been tested in pulmonary fibrosis models, and an antagonist of LPAR1 (AM095) in bleomycin (BLM)-induced pulmonary fibrosis. Both compounds abrogated the development of pulmonary fibrosis and prevented the distortion of lung architecture, exhibiting qualitative and quantitative differences in different manifestations of the modeled disease.

Physiologically Based Pharmacokinetic Modeling of Fimasartan, Amlodipine, and Hydrochlorothiazide for the Investigation of Drug-Drug Interaction Potentials.

PURPOSE: To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug-drug interaction (DDI) potentials. METHODS: The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model. RESULTS: The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide. CONCLUSIONS: The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.