The syntheses and in vitro biotransformation studies of [14C]apixaban,a highly potent,selective, efficacious and orally bioavailable inhibitor of blood coagulation Factor Xa

Apixaban is a potent inhibitor of blood coagulation Factor Xa in the late stages of development. [¹⁴C]apixaban was synthesized with the 14C label in the two different lactam ring systems within the molecule for various in vitro and in vivo metabolism studies. A nine‐step synthesis of [¹⁴C]apixaban, 10 , with the label in the central lactam ring was completed in 14% overall yield. A second synthesis of [¹⁴C]apixaban, 14 , with the 14C label in the outer lactam ring was completed in three steps in a 14% overall yield. No significant differences were observed between the metabolite profiles of 10 and 14 , [¹⁴C]apixaban, from both rat and human hepatocyte or microsomal incubations. Copyright © 2011 John Wiley & Sons, Ltd.     

雷公藤的肝毒性研究及ADME/Tox评价思路

雷公藤Triptergium wilfordii为卫矛科植物,具有多种药理作用,作为一种传统常用中药,其临床应用广泛,疗效显著,但使用中引起的肝损伤报道频繁发生.作为一种有毒中药,雷公藤本身所含化学成分多而复杂,且化合物多存在同物异名现象.现就雷公藤所含成分进行总结,并从相关临床病例报道出发,对雷公藤所致肝损害的特点及其可能的作用机制进行综述,提出基于ADME/Tox评价中药肝毒性的研究新思路,在原有的病理表征等传统研究方法的基础上,开展更为细致的中药毒性物质基础的研究.     

Organ/body-on-a-chip based on microfluidic technology for drug discovery

Although animal experiments are indispensable for preclinical screening in the drug discovery process, various issues such as ethical considerations and species differences remain. To solve these issues, cell-based assays using human-derived cells have been actively pursued. However, it remains difficult to accurately predict drug efficacy, toxicity, and organs interactions, because cultivated cells often do not retain their original organ functions and morphologies in conventional in vitro cell culture systems. In the μTAS research field, which is a part of biochemical engineering, the technologies of organ-on-a-chip, based on microfluidic devices built using microfabrication, have been widely studied recently as a novel in vitro organ model. Since it is possible to physically and chemically mimic the in vitro environment by using microfluidic device technology, maintenance of cellular function and morphology, and replication of organ interactions can be realized using organ-on-a-chip devices. So far, functions of various organs and tissues, such as the lung, liver, kidney, and gut have been reproduced as in vitro models. Furthermore, a body-on-a-chip, integrating multi organ functions on a microfluidic device, has also been proposed for prediction of organ interactions. We herein provide a background of microfluidic systems, organ-on-a-chip, Body-on-a-chip technologies, and their challenges in the future.     

Chromanyl–isoxazolidines as Antibacterial agents: Synthesis,Biological Evaluation,Quantitative Structure Activity Relationship,and Molecular Docking Studies

Regio‐ and stereoselective 1,3‐dipolar cycloadditions of C‐(chrom‐4‐one‐3‐yl)‐N‐phenylnitrones ( N ) with different mono‐substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N‐phenyl‐3′‐(chrom‐4‐one‐3‐yl)‐isoxazolidines ( 1‐40 ). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium‐1 & Salmonella typhymurium‐2 with minimum inhibitory concentration value of 1.56 μ g/mL and also showed good potential against methicillin‐resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μ g/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities.     

Disposition and metabolism of [14C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor,in healthy subjects

1.?Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor.

2.?Following oral administration, [¹⁴C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5–1?h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ～1.3, ～12 and ～21?h, respectively.

3.?Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7–67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ～85.5% of the total dose.

4.?Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.     

Development and Qualification of a Physiologically Based Pharmacokinetic Model of Finasteride and Minoxidil Following Scalp Application

In this study, we aimed to develop and qualify a PBPK model for scalp application using two drugs with marked differences in physicochemical properties and PK profiles. The parameters related to scalp physiology, drug PK, and formulations were incorporated into a Multi-Phase and Multi-Layer (MPML) Mechanistic Dermal Absorption (MechDermA) model within the Simcyp® Simulator V17. The finasteride PBPK model was linked to its effect on dihydrotestosterone (DHT) levels in plasma and scalp using an indirect response model. Predicted PK (and PD for finasteride) profiles and parameters were compared against the clinically reported data and justified by visual predictive checks and two-fold error criteria for model verification. The PBPK/PD model for finasteride reasonably demonstrated an ability to predict its respective PK and PD profiles, and parameters following scalp application under various clinical scenarios. Using the same scalp physiological input parameters, the minoxidil PBPK model was then developed and satisfactorily qualified with independent clinical datasets. Collectively, these results suggested that the established PBPK model may have broader utility for other topical formulations intended for scalp application.     

In the search for a lead structure among series of potent and selective hydantoin 5‐HT7R agents: The drug‐likeness in vitro study

Since the year 1993, when 5‐HT₇ receptor (5‐HT₇R) was discovered, there is no selective 5‐HT₇R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5‐HT₇R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by “drug‐likeness” estimation of the first series of selective and potent 5‐HT₇R ligands among 5‐(4‐fluorophenyl)‐3‐(2‐hydroxy‐3‐(4‐aryl‐piperazin‐1‐yl)propyl)‐5‐methylimidazolidine‐2,4‐dione derivatives ( 11–16 ). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2 . The experiments showed promising drug‐like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13 . The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant‐like activity in the FST. Taking into account the beneficial properties of 13 , i.e., good drug‐like parameters, the significant antagonistic action, high selectivity to 5‐HT₇R, and its in vivo antidepressant‐like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5‐HT₇ receptor.     

Metabolism,excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration

1.?The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100?mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2.?The peak concentrations of glasdegib (890.3?ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75?hours post-dose. The AUC_inf were 8469?ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3.?Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120?hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4.?Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.     

Disposition of the emerging brominated flame retardant,bis(2-ethylhexyl) tetrabromophthalate,in female Sprague Dawley rats: effects of dose,route and repeated administration

1.?Bis(2-ethylhexyl)-tetrabromophthalate (BEH-TEBP; CAS No. 26040-51-7; PubChem CID: 117291; MW 706.15?g/mol, elsewhere: TeBrDEPH, TBPH, or BEHTBP) is used as an additive brominated flame retardant in consumer products.

2.?Female Sprague Dawley rats eliminated 92–98% of [¹⁴C]-BEH-TEBP unchanged in feces after oral administration (0.1 or 10?μmol/kg). A minor amount of each dose (0.8–1%) was found in urine after 72?h. Disposition of orally administered BEH-TEBP in male B6C3F1/Tac mice was similar to female rats.

3.?Bioaccumulation of [¹⁴C]-radioactivity was observed in liver and adrenals following 10 daily oral administrations (0.1?μmol/kg/day). These tissues contained 5- and 10-fold higher concentrations of [¹⁴C]-radioactivity, respectively, versus a single dose.

4.?IV-administered [¹⁴C]-BEH-TEBP (0.1?μmol/kg) was slowly eliminated in feces, with?>15% retained in tissues after 72?h. Bile and fecal extracts from these rats contained the metabolite mono-ethylhexyl tetrabromophthalate (TBMEHP).

5.?BEH-TEBP was poorly absorbed, minimally metabolized and eliminated mostly by the fecal route after oral administration. Repeated exposure to BEH-TEBP led to accumulation in some tissues. The toxicological significance of this effect remains to be determined. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476).     

The biological fate of decabromodiphenyl ethane following oral,dermal or intravenous administration

1.?It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume.

2.?In the present study, female Sprague Dawley rats were administered a single dose of [¹⁴C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [¹⁴C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose.

3.?DBDPE was poorly absorbed following oral dosing, with 95% of administered [¹⁴C]-radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72?h. DBDPE excretion was similar in male mice and female rats. Accumulation of [¹⁴C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats.

4.?Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ～14?±?8% of DBDPE may be absorbed into human skin in vivo; ～7?±?4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24?h).

5.?Following intravenous administration, ～70% of the dose remained in tissues after 72?h, with the highest concentrations found in lung (1223?±?723?pmol-eq/g), spleen (1096?±?369?pmol-eq/g) and liver (366?±?98?pmol-eq/g); 5?±?1% of the dose was recovered in urine and 26?±?4% in the feces.