RT Journal Article
SR Electronic
T1 PIMECROLIMUS: ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION IN HEALTHY VOLUNTEERS AFTER A SINGLE ORAL DOSE AND SUPPLEMENTARY INVESTIGATIONS IN VITRO
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 765
OP 774
DO 10.1124/dmd.105.007732
VO 34
IS 5
A1 Zollinger, Markus
A1 Waldmeier, Felix
A1 Hartmann, Stefan
A1 Zenke, Gerhard
A1 Zimmerlin, Alfred G.
A1 Glaenzel, Ulrike
A1 Baldeck, Jean-Pierre
A1 Schweitzer, Alain
A1 Berthier, Stephane
A1 Moenius, Thomas
A1 Grassberger, Maximilian A.
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/765.abstract
AB The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [3H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After tmax (1–3 h), its blood concentrations fell quickly to 3% of Cmax at 24 h, followed by a slow terminal elimination phase (average t1/2 62 h). Radioactivity in blood decreased more slowly (8% of Cmax at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve0–24 h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus. The American Society for Pharmacology and Experimental Therapeutics