biphenylylacetic-acid and Disease-Models--Animal

Drug‑induced liver injury (DILI) is a common hepatic disease. The identification of biomarkers for DILI prediction is critical for rational drug use. The aim of the present study was to investigate liver injury caused by binaprofen and identify proteins that may serve as early biomarkers to predict DILI. For in vivo DILI assays, zebrafish were exposed to acetaminophen (APAP) and binaprofen for 12‑96 h before lethal concentration 50 (LC50), histopathological analysis, conventional and non‑conventional biomarker measurements were conducted. In vitro assays were performed in cultured liver cells; after 6‑24 h treatment with APAP and binaprofen the same measurements were conducted as aforementioned. The in vivo assays indicated that the LC50 of APAP was 5.2 mM, whereas the LC50 of binaprofen was 1.2 mM; 12‑48 h post‑treatment, liver cells exhibited mild to moderate vacuolization in a time‑ and concentration‑dependent manner in response to both drugs. During this time, conventional and non‑conventional biomarkers were also altered in a time‑ and concentration‑dependent manner; however, alterations in the levels of non‑conventional biomarkers occurred at an earlier time point compared with conventional biomarkers. The in vitro assays indicated that the half maximal inhibitory concentration (IC50) of APAP was 16.2 mM, whereas the IC50 of binaprofen was 5.3 mM; 12‑48 h post‑treatment, cultured liver cells exhibited mild to moderate swelling in a time‑ and concentration‑dependent manner. Alterations in the levels of conventional and non‑conventional biomarkers were similar to those observed in the in vivo assays. As a non‑steroidal anti‑inflammatory drug, binaprofen exhibited expected levels of liver toxicity in in vitro and in vivo assays, which were similar to APAP. Total bile acid and argininosuccinate lyase were identified as early biomarkers, which could accurately predict onset of binaprofen‑induced liver injury.

Topics: Animals; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Female; Immunohistochemistry; Liver Function Tests; Male; Phenylacetates; ROC Curve; Zebrafish

Novel mutual prodrugs of biphenylacetic acid were designed as a promising gastro-protective alternative to fenbufen. Biphenyacetic acid was covalently linked with two non-essential amino acids (D-phenylalanine and glycine) possessing wound healing, analgesic, and anti-inflammatory properties. The prodrugs exhibited good stability in stomach homogenates while hydrolytic release of biphenylacetic acid was observed in phosphate buffer, small intestinal homogenates, and 80% human plasma. In vivo behavior of prodrugs on oral administration to Wistar rats demonstrated 33-45% release of biphenylacetic acid in blood over a period of 24 h indicating passage of intact prodrugs to colon, colonic release of parent drug followed by its absorption through colonic mucosa into systemic circulation. Prodrugs were extensively evaluated for analgesic, anti-inflammatory, anti-arthritic, and ulcerogenic activities. Biochemical, haemetological, histopathological, and radiological studies were also performed. Conversion of bioprecusor fenbufen into mutual carrier-linked prodrugs proved to be promising alternative in terms of reduced ulcerogenic propensity, longer duration of analgesia, enhanced/prolonged anti-inflammatory activity, and superior anti-arthritic effect. These prodrugs could be developed further for chronotherapy of rheumatoid arthritis.

Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Disease Models, Animal; Drug Liberation; Female; Glycine; Humans; Inflammation; Male; Pain; Phenylacetates; Phenylalanine; Phenylbutyrates; Prodrugs; Rats; Rats, Wistar

Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.

Topics: Animals; Biological Availability; Disease Models, Animal; Dogs; Drug Discovery; Mice; Phenylacetates; Rats; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Perennial