title: Carrier-linked mutual prodrugs of biphenylacetic acid as a promising alternative to bioprecursor fenbufen: design, kinetics, and pharmacological studies.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, 411038, Maharashtra, India, suneeladhaneshwar@rediffmail.com.
authors.forename: Suneela
authors.initials: S
authors.lastname: Dhaneshwar
authors.forename: Manisha
authors.initials: M
authors.lastname: Kusurkar
authors.forename: Subhash
authors.initials: S
authors.lastname: Bodhankar
authors.forename: Gopal
authors.initials: G
authors.lastname: Bihani
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D065546:Drug Liberation; D005260:Female; D005998:Glycine / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D010649:Phenylalanine / Q000737:chemistry; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010648:Phenylacetates; D010654:Phenylbutyrates; D011355:Prodrugs; D010649:Phenylalanine; C012776:biphenylylacetic acid; C010725:fenbufen; D005998:Glycine