Translational Pharmacokinetic Modeling of Fingolimod (FTY720) as a Paradigm Compound Subject to Sphingosine Kinase-Mediated Phosphorylation

• Published in: Drug metabolism and disposition Vol. 42; no. 9; pp. 1367 - 1378
• Main Authors: Snelder, Nelleke, Ploeger, Bart A., Luttringer, Olivier, Stanski, Donald. R., Danhof, Meindert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014
• Subjects: Administration, Intravenous; Administration, Oral; Animals; Blood Platelets - metabolism; Double-Blind Method; Fingolimod Hydrochloride; Humans; Lysophospholipids - metabolism; Male; Phosphates - metabolism; Phosphorylation - drug effects; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Propylene Glycols - administration & dosage; Propylene Glycols - pharmacokinetics; Randomized Controlled Trials as Topic; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacokinetics; Km; S1P; Vin vivo; fingolimod-P; ka; Vm; PBPK; Kd; PK; S1PHK; LOQ

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through their respective phosphate metabolites, which are formed by the enzyme sphingosine kinase (S1PHK). In this investigation, we present a semimechanistic p...