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Assessment of absorption of RHO kinase inhibitor fasudil at different sites of the human gastrointestinal tract
Author(s) -
Lu M.,
Tao B.,
Pawula M.,
Karara A.,
Wilding I.,
Hinderling P. H.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.023
Subject(s) - fasudil , cmax , ascending colon , pharmacology , pharmacokinetics , ileum , absorption (acoustics) , medicine , gastrointestinal tract , chemistry , gastroenterology , biochemistry , rho associated protein kinase , kinase , materials science , composite material
Purpose Fasudil, a novel Rho kinase inhibitor, is being developed for treatment of angina. This study evaluated the gastrointestinal (GI) absorption of fasudil at different sites using Enterion™ capsules and assessed the feasibility of developing an extended release (ER) formulation. Method Eight healthy male volunteers completed this single dose, open label, randomized, 5‐way crossover study. 40 mg fasudil HCl was administered as: solution to the distal ileum and ascending colon, powder to the ascending colon, oral solution, and IR tablets. There was a 3‐day washout between treatments. Results All treatments were well tolerated and no serious AEs were observed. Fasudil was rapidly metabolized to its major active metabolite M3 and fasudil concentrations were negligible following the GI absorption. The results of pharmacokinetic analysis for M3 are shown below.(see Table) Conclusion The systemic availability of M3 is similar throughout the selected gastrointestinal sites, thus supporting the feasibility of developing an ER formulation for once daily dose. Clinical Pharmacology & Therapeutics (2004) 75 , P6–P6; doi: 10.1016/j.clpt.2003.11.023Parameter (Mean ± SD) Ileum Solution Colon Solution Colon Powder Oral Solution Oral TabletCmax (ng/mL) 139 (46.6) 87.8 (37.7) 77.0 (33.5) 120 (32.5) 129 (66.9) Tmax (h) 0.62 (0.19) 0.92 (0.73) 0.96 (0.70) 0.70 (0.25) 0.75 (0.27) T1/2 (h) 5.31 (0.88) 6.13 (1.56) 6.86 (3.29) 5.25 (0.53) 5.50 (0.87) AUC (ng * h/mL) 323 (46.8) 340 (63.1) 383 (126) 300 (45.1) 308 (76.3) F * 1.04 (0.13) 1.14 (0.21) 1.27 (0.33) 1.04 (0.26)* Relative bioavailability compared to oral solution.