[Mechanisms of pharmacokinetic drug-drug interactions].
Pharmacokinetic drug-drug interactions occur when a drug alters the disposition (absorption, distribution, elimination) of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters. The increase of drug plasma concentrations is generally related to the inhibition of enzymes and/or drug transport. The decrease of drug concentrations reflects the activation of orphan nuclear receptors by inducers that lead to the increase of the expression of enzymes and drug transporters. Inhibition of drug metabolism or transport is quite immediate (24-48h) while induction is a slower process (7-10 days). Complex situations may be observed with drugs that are both inducers and inhibitors (rifampin, ritonavir). They can cause the decrease and the increase of the exposure of the combined agent depending on the duration of the association.
Levêque
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Service de pharmacie, hôpital Hautepierre, hôpitaux universitaires de Strasbourg, avenue Molière, 67000 Strasbourg, France. dominique.leveque@chru-strasbourg.fr <dominique.leveque@chru-strasbourg.fr>
Lemachatti
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Nivoix
Y
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Coliat
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P
Santucci
R
R
Ubeaud-Séquier
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G
Beretz
L
L
Vinzio
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D000284:Administration, Oral; D000890:Anti-Infective Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004798:Enzymes / Q000235:genetics; D004917:Erythromycin / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007408:Intestinal Absorption; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013997:Time Factors
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004798:Enzymes; D026901:Membrane Transport Proteins; D057093:Orphan Nuclear Receptors; D004364:Pharmaceutical Preparations; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System