Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro.
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 [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) 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 curve(0-24) 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.
Zollinger
Markus
M
Novartis Pharma AG, WKL-135.2.21, P.O. box, CH-4002 Basel, Switzerland. markus.zollinger@novartis.com
Waldmeier
Felix
F
Hartmann
Stefan
S
Zenke
Gerhard
G
Zimmerlin
Alfred G
AG
Glaenzel
Ulrike
U
Baldeck
Jean-Pierre
JP
Schweitzer
Alain
A
Berthier
Stephane
S
Moenius
Thomas
T
Grassberger
Maximilian A
MA
D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D001773:Blood Cells / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D017930:Genes, Reporter / Q000235:genetics; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000235:genetics; D007408:Intestinal Absorption; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D016559:Tacrolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007527:Isoenzymes; C117268:pimecrolimus; D003577:Cytochrome P-450 Enzyme System; D016559:Tacrolimus