Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs.
OBJECTIVE
To investigate the in vitro metabolism of the antithrombotic agent fondaparinux sodium in mammalian liver fractions and to evaluate its potential inhibitory effect on human cytochrome P450 (CYP)-mediated metabolism of other drugs.


METHODS
Metabolism was evaluated by incubating radioisotope-labelled fondaparinux sodium with postmitochondrial liver fractions of rat, rabbit, monkey or human origin (three subjects). Human liver microsomal preparations and an NADPH-generating system were incubated with phenacetin, coumarin, tolbutamide, S-mephenytoin, bufuralol, chlorzoxazone or nifedipine. These are selectively metabolised by CYP isoforms: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, respectively. Experiments were designed to determine apparent K(i) (inhibitory constant) values for fondaparinux sodium against each CYP isoform, by varying concentrations of fondaparinux sodium and the selective substrate. Each experiment included control reaction mixtures containing an isoform-selective inhibitor. After incubation, the mixtures were analysed by LC-MS/MS or with fluorometric detection.


RESULTS
All liver fractions were enzymatically active, as demonstrated by degradation of [(14)C]testosterone. No metabolism of fondaparinux sodium was detectable in postmitochondrial liver fractions. Apparent K(i) values for fondaparinux sodium against the CYP isoforms could not be determined because the oxidative metabolism of the isoform-selective CYP substrates was not significantly inhibited in pooled microsomal reaction mixtures. In the presence of selective CYP inhibitors, metabolism of each substrate was significantly reduced, confirming that inhibition could be observed in these assays.


CONCLUSIONS
The demonstrated lack of mammalian hepatic metabolism of fondaparinux sodium is consistent with animal and human studies. The absence of inhibition of the human CYP isoforms commonly involved in the metabolism of drugs suggests that clinical treatment with fondaparinux sodium is unlikely to interfere with the pharmacokinetics and metabolism of a wide range of other drugs which are associated with CYP inhibition.
Lieu
Carolyne
C
Sanofi-Synthelabo Research Division, Great Valley, Pennsylvania, USA.
Shi
Juan
J
Donat
François
F
Van Horn
Robert
R
Brian
William
W
Newton
John
J
Delbressine
Leon
L
Vos
Ria
R
D000328:Adult; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005343:Fibrinolytic Agents / Q000378:metabolism* / Q000494:pharmacology; D000077425:Fondaparinux; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D005343:Fibrinolytic Agents; D007527:Isoenzymes; D011134:Polysaccharides; D003577:Cytochrome P-450 Enzyme System; D000077425:Fondaparinux