Pharmacokinetics,pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.     

Establishing maximum tolerated doses for a 2-year combined chronic/carcinogenicity rat study based on toxicokinetic and toxicity gender differences

For agrochemicals tested in a carcinogenicity rodent study, it is often not possible to use the same high dose to achieve maximum tolerated dose (MTDs) without overdosing or insufficiently challenging one gender if significant gender differences are known. Toxicokinetic (TK) data for pesticide FR from a 28-day rat study showed that males required a 3-fold higher external dose compared to females to produce similar internal exposure levels of the parent compound. In the 90-day study, 8%/17% (M/F) decrease in bodyweight gain (BWG) and 15%/15% (M/F) increase in relative liver weights were observed in the 6000 ppm males and 2000 ppm females, respectively. Based on the above TK and toxicity data, different high dose levels were selected for females (1600 ppm) and males (4800 ppm) for a 2-year combined chronic/carcinogenicity study in rats. In the 2-year study, 14%, 13%, 13% and 21% reduction in BWG of males and 10%, 12%, 19% and 20% reduction in BWG of females were observed at weeks 13, 26, 52 and 104, respectively in the highest dose tested. Similar reductions in bodyweight gain in males and females at the different high dose levels clearly demonstrated that appropriate MTDs were reached. Therefore, it is scientifically sound and practical to use TK and toxicity data to use different high dose levels to achieve MTDs for a pesticide with large gender differences.     

The Acquisition and Application of Absorption,Distribution, Metabolism,and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.     

Importance of cynomolgus monkeys in development of monoclonal antibody drugs

Animal species used in the preclinical studies for development of monoclonal antibody (mAb) drugs are surveyed in this review. Relevant animal species for preclinical studies of mAb candidates are those express desired epitope of mAb candidates. Cynomolgus monkeys cross-react with mAb drugs much higher than other animal species commonly used in preclinical studies such as absorption, distribution, metabolism and excretion (ADME), efficacy, and toxicity studies, for development of new drugs. Moreover, plasma exposure of the mAb drugs in humans is predicted well from the exposure in the monkeys, and the placental transfer of immunoglobulin G (IgG, all the mAb drugs contain IgG) from mother to fetus is similar between humans and the monkeys from a viewpoint of time course and plasma level of IgG transferred. These observed findings indicate that the monkeys are the most suitable animal species used in the ADME and toxicity studies for development of new mAb drugs.     

The mesentery: an ADME perspective on a ‘new’ organ

Abstract

With the inclusion of mesentery, the total number of human organs has recently increased by one. The mesentery was formerly construed to be a complex, discontinuous anatomical structure simply serving as a support for organs in abdominal cavity. However, recent research has established the mesentery to be a far more simple and unfragmented organ. Newly emerging information on the mesentery has challenged some older pathophysiological concepts. This review briefly discusses the anatomy of the mesentery, historical perspective on the mesentery, embryology, drug metabolizing enzymes and transporters of the mesentery, and the mesentery’s role in diseases. The possible impact of the mesentery on absorption, distribution, metabolism, and excretion (ADME) is also discussed.     

Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract

Abstract

1. The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach.

2. In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism. The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability. Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA. Ex vivo precipitation studies with the stomach content of fasted rats were also carried out. Fitting procedures were performed with NONMEM VII 1.2.

3. The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes. The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations. Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded. The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution. Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo.     

Role of iodine in the toxicity of diiodomethyl-p-tolylsulfone (DIMPTS) in rats: ADME

Metabolism of diiodomethyl-p-tolylsulfone (DIMPTS) was investigated in rats to determine the role of iodide in its toxicity. Fischer 344 (F-344) (5 or 50 mg/kg) or Sprague Dawley (SD) (5 mg/kg) rats were gavaged with ¹⁴C-DIMPTS or dermally applied with 5 mg/kg (F-344 only) and absorption, distribution, metabolism and excretion (ADME) determined. Additional experiments were conducted with its deiodinated analog (methyl-p-tolylsulfone, MPTS) in female F-344 rats (20 mg/kg) for comparison. Orally administered ¹⁴C-DIMPTS was rapidly absorbed and eliminated in urine (92%). The elimination t_½ was 1–4 h. Dermally applied ¹⁴C-DIMPTS remained undetectable in plasma with bioavailability ∼7%, only 5–7% of the dose was recovered in urine. DIMPTS liberated one or both of its iodine atoms upon absorption. The rate of elimination of the liberated iodide from the systemic circulation was 2- to 3-fold slower in SD than F-344 rats, which resulted in higher bioavailability of iodide to SD rats. DIMPTS was primarily oxidized at the benzylic methyl moiety forming the corresponding benzoic acid. Glutathione conjugation on the sulfonyl methyl group, via displacement of I⁻ was also observed. Overall 67–80% of the total iodine atoms were metabolically released from DIMPTS. The MPTS was rapidly absorbed from the GI tract, metabolized and eliminated in urine similar to that of DIMPTS. These data were compared to iodide toxicokinetic results of a reproductive toxicity study for DIMPTS (80 mg/kg/day) and MPTS (32 mg/kg/day), where DIMPTS was toxic to dams and pups, while MPTS caused no toxicity. These data show that the liberated iodide is the ultimate toxicant of DIMPTS, which is readily transported to pups through milk, while the methyltolylsulfone backbone structure (MPTS) of DIMPTS is relatively nontoxic.     

Synthesis and evaluation of 2(3H)-thiazole thiones as tyrosinase inhibitors

A series of 2(3H)-thiazole thiones 3-5 was synthesized and evaluated for tyrosinase inhibition and DPPH radical scavenging activities. Among them, 3-methyl-4-phenyl-2(3H)-thiazole thione (4a) showed good tyrosinase inhibitory activity, even better than that of the well-known tyrosinase inhibitor, namely, kojic acid. From the structure-activity point of view, although it was found that the phenolic hydroxyl group in prototype 3-5 might contribute to the scavenging activity against DPPH radicals, there was no correlation between the potency of tyrosinase inhibition and the presence of the phenolic moiety. The in silico ADME-Tox screening revealed that the drug-likeness and drug-score values of the most potent compound 4a were significantly higher than those of kojic acid.     

Novel bis-(-)-nor-meptazinol derivatives act as dual binding site AChE inhibitors with metal-complexing property

The strategy of dual binding site acetylcholinesterase (AChE) inhibition along with metal chelation may represent a promising direction for multi-targeted interventions in the pathophysiological processes of Alzheimer's disease (AD). In the present study, two derivatives (ZLA and ZLB) of a potent dual binding site AChE inhibitor bis-(−)-nor-meptazinol (bis-MEP) were designed and synthesized by introducing metal chelating pharmacophores into the middle chain of bis-MEP. They could inhibit human AChE activity with IC₅₀ values of 9.63 μM (for ZLA) and 8.64 μM (for ZLB), and prevent AChE-induced amyloid-β (Aβ) aggregation with IC₅₀ values of 49.1 μM (for ZLA) and 55.3 μM (for ZLB). In parallel, molecular docking analysis showed that they are capable of interacting with both the catalytic and peripheral anionic sites of AChE. Furthermore, they exhibited abilities to complex metal ions such as Cu(II) and Zn(II), and inhibit Aβ aggregation triggered by these metals. Collectively, these results suggest that ZLA and ZLB may act as dual binding site AChEIs with metal-chelating potency, and may be potential leads of value for further study on disease-modifying treatment of AD.