title: Topical delivery of leflunomide for rheumatoid arthritis treatment: evaluation of local tissue deposition of teriflunomide and its anti-inflammatory effects in an arthritis rat model.
abstract: OBJECTIVE
  We investigated whether leflunomide can be delivered topically and metabolized into teriflunomide through the skin, and evaluated the therapeutic effect of topical leflunomide.
  
  
  METHODS
  Permeation of leflunomide across and formation of its active metabolite within the skin was examined ex vivo. Deposition of teriflunomide in micropig knee joints after applying topical and transdermal patches containing leflunomide was investigated by determining the plasma and joint tissue concentrations. Finally, the anti-inflammatory effects and inhibition of skin sensitization by topical leflunomide were evaluated in a rat adjuvant arthritis model and mice with delayed-type induced hypersensitivity.
  
  
  RESULTS
  We found that after topical application of leflunomide on freshly excised mouse, rat and guinea pig skin, ∼24% of the permeated drug existed as teriflunomide. In micropigs treated topically with leflunomide on the knee joint, significantly lower teriflunomide concentrations were found in plasma, but its concentrations in the knee joint were 3.4-fold to 54.6-fold higher than those after oral administration. In a rat arthritis model, the plasma concentration of teriflunomide after treatment with 10% leflunomide topical solution was 7.54-fold lower than that after 10 mg/kg oral leflunomide. However, topical leflunomide was nearly as effective as oral in inhibiting paw edema (37% versus 56%, respectively). The values for hypersensitized mouse ear weight after treatment with topical leflunomide decreased significantly by 26% compared to vehicle.
  
  
  CONCLUSIONS
  These results demonstrate that topically applied leflunomide can be delivered effectively and deposited as teriflunomide in an arthritic joint, possibly allowing better compliance in rheumatoid arthritis patients by avoiding leflunomide's side effects.
authors.affiliation: a Amorepacific Corporation R&D Center , Yongin-si, Gyeonggi-do , Republic of Korea and.
authors.forename: Joonho
authors.initials: J
authors.lastname: Bae
authors.affiliation: b College of Pharmacy and Natural Medicine Research Institute, Mokpo National University , Muan-gun, Jeonnam , Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D003437:Crotonates / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006168:Guinea Pigs; D006885:Hydroxybutyrates; D007555:Isoxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077339:Leflunomide; D051379:Mice; D008812:Mice, Hairless; D008807:Mice, Inbred BALB C; D009570:Nitriles; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution; D014052:Toluidines / Q000493:pharmacokinetics; D057968:Transdermal Patch
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003437:Crotonates; D006885:Hydroxybutyrates; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D000077339:Leflunomide
keywords: Leflunomide; rheumatoid arthritis; teriflunomide; topical delivery; transdermal