title: Cross-species comparisons of the pharmacokinetics of ibudilast.
abstract: To enable clinical development of ibudilast for new indications, its pharmacokinetics were characterized in mice, rats, rabbits, dogs, cynomolgus monkeys, and minipigs. Animal pharmacokinetics were compared with a separate study in healthy volunteers. Following oral dosing, the dose-normalized area under the curve (AUC) (DN-AUC(24h)) in humans is 896 ((ng*h ml(-1))/(mg kg(-1))), and in animals ranges from 0.3 to 87. The variability among species cannot be explained by intrinsic clearance, which in intravenous dosing experiments shows only moderate interspecies variation (13-41 l h(-1) m(-2)). A portal vein rat pharmacokinetics model suggested that differences in first-pass gut clearance may explain some of the interspecies variation in oral bioavailability. Ibudilast shows auto-induction of metabolism in some animals, but not in humans. Plasma protein binding in humans and some animals is greater than or equal to 95%. The primary metabolite 6,7-dihyrdodiol-ibudilast is measurable and has been quantitated in plasma from animals and humans. Finally, biodistribution studies show that ibudilast distributes rapidly, extensively, and reversibly to the central nervous system.
authors.affiliation: Research and Development, Avigen Inc., 1301 Harbor Bay Parkway, Alameda, CA 94502, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Sanftner
authors.forename: J A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: M I
authors.initials: MI
authors.lastname: Gross
authors.forename: B M
authors.initials: BM
authors.lastname: Suzuki
authors.forename: F C A
authors.initials: FC
authors.lastname: Gaeta
authors.forename: K W
authors.initials: KW
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013045:Species Specificity; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D001798:Blood Proteins; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles