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Titolo:
Inhibition of phenytoin hydroxylation in human liver microsomes by severalselective serotonin re-uptake inhibitors
Autore:
Nelson, MH; Birnbaum, AK; Remmel, RP;
Indirizzi:
Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 d Chem, Minneapolis, MN 55455 USA Univ Minnesota, Coll Pharm, Dept Expt & Clin Pharmacol, Minneapolis, MN 55455 USA Univ Minnesota Minneapolis MN USA 55455 rmacol, Minneapolis, MN 55455 USA
Titolo Testata:
EPILEPSY RESEARCH
fascicolo: 1, volume: 44, anno: 2001,
pagine: 71 - 82
SICI:
0920-1211(200104)44:1<71:IOPHIH>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
REUPTAKE INHIBITORS; IN-VITRO; CYTOCHROME P4502C9; DRUG-INTERACTIONS; METABOLISM; FLUOXETINE; PHARMACOKINETICS; ANTIDEPRESSANTS; SULFAPHENAZOLE; PHARMACOLOGY;
Keywords:
drug interactions; phenytoin; selective serotonin re-uptake inhibitors; human liver microsomes; anti-epileptic drugs;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Remmel, RP SW Oklahoma State Univ, Sch Pharm, Dept Pharmaceut Sci, 100 Campus Dr, Weatherford, OK 73096 USA SW Oklahoma State Univ 100 Campus Dr Weatherford OK USA 73096 A
Citazione:
M.H. Nelson et al., "Inhibition of phenytoin hydroxylation in human liver microsomes by severalselective serotonin re-uptake inhibitors", EPILEPSY R, 44(1), 2001, pp. 71-82

Abstract

Several case reports have indicated that the selective serotonin re-uptakeinhibitor (SSRI) fluoxetine increases phenytoin blood levels when given concurrently. The mechanism of this drug-drug interaction has been attributedto inhibition of CYP2C9-catalyzed hydroxylation of phenytoin to its major oxidative metabolite in humans, para-hydroxyphenyl phenyl hydantoin (HPPH). With a bank of human liver microsomes (HLM), four SSRIs (fluoxetine, norfluoxetine, sertraline, and paroxetine) were tested for inhibition of HPPH formation. Initially, the K-m and V-max values of phenytoin hydroxylation to HPPH were determined in the individual HLM samples. The average K-m (n = 8)was 9.7 +/- 2.9 muM. The V-max varied fivefold, with an average value of 113 +/- 53 pmol HPPH/min/nmol CYP450. All of the SSRIs inhibited HPPH formation; resulting Ki values were 31.1 +/- 10.1 muM (fluoxetine) (n = 5), 51.1 /- 9.4 muM (norfluoxetine) (n = 3), 52.2 +/- 21.5 muM (sertraline) (n = 3), and 80.0 +/- 7.2 muM (paroxetine) (n = 3). Sulfaphenazole (10 muM), utilized as a positive control for inhibition of HPPH formation, inhibited phenytoin hydroxylation (> 95%) in all HLM samples. Diclofenac hydroxylation to 4'-OH diclofenac, a specific marker for CYP2C9 activity, was determined in HLM1-HLM6 and was highly correlated with HPPH formation in HLM1-HLM6, indicating that phenytoin hydroxylation in human liver microsomes is largely dueto CYP2C9. This work presents direct evidence that the effect of fluoxetine on phenytoin blood levels may be explained by inhibition of CYP2C9-catalyzed phenytoin hydroxylation. In light of typical SSRI blood levels observedin patients, this study also suggests that the risk of a SSRI-phenytoin interaction is highest with fluoxetine and norfluoxetine, and less paroxetine. (C) 2001 Elsevier Science B.V. All rights reserved.

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Documento generato il 24/01/20 alle ore 12:27:44