Metabolism alprazolam

Tr/azo/obenzocf/azep/nes-Triazolam and alprazolam, metabolized by cytochrome P-450 3A4, have increased plasma concentrations when administered concomitantly with nefazodone. If triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage is recommended. It is recommended that triazolam not be used in combination with nefazodone. No dosage adjustment is required for nefazodone. 

Sertraline (50-150 mg/day) had no effects on alprazolam metabolism in a randomized, double-blind, placebo-con-trolled study in 10 healthy volunteers (24). 

Inhibition of alprazolam metabolism by dextropropoxyphene has been reported (37). 

The concurrent use of fluoxetine 60 mg daily has been found to reduce the clearance of alprazolam 1 mg four times daily by about 21% and to increase its plasma levels by about 30%. These changes were accompanied by increased psychomotor impairment. This appears to be due to reduced alprazolam metabolism. Another study also reported impaired alprazolam metabolism, considered to be due to the inhibition of cytochrome P450 isoenzyme CYP3A4 by fluoxetine, although no significant changes in alprazolam pharmacodynamics were found. ... 

No important changes in the pharmacokinetics of paroxetine were seen when 12 healthy subjects given paroxetine 30 mg daily were also given diazepam 5 mg three times a day. Adverse events were not inereased by the combination. In another study it was foimd that paroxetine did not increase the impairment of a number of psychomotor tests eaused by oxazepam.In vitro studies using human liver mierosomal enzymes have shown that paroxetine is a relatively weak inhibitor of alprazolam metabolism mediated by the cytochrome P450 subfamily CYP3A. Furthermore, a randomised, placebo-controlled study in 22 healthy subjeets reported no evidence for a pharmacokinetic or pharmacological interaction between paroxetine and alprazolam. ... 

Benzodiazepines (alprazolam) COCs may inhibit oxidative metabolism Increase side effects of benzodiazepines... 

The structures of the drugs used as a small test set for the model are listed in Table 17.1. Loperamide and asimadoline are P-gp substrates terfenadine and ebastine are compounds that are rapidly metabolized alprazolam, dobazam, di-and mono-hydroxy-L66858 [11] are benzodiazepines testosterone and corticosterone are hormones and cefadroxyl, cefaclor, cephalotin and cefmetazole are cephalosporins [12]. Finally, peptides 1 to 10 are peptidomimetic drugs [13]. 

Yuan R, Flockhart DA, Balian JD Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999,39 1109-1125. 

Pai HV, Upadhya SC, Chinta SJ, Hegde SN, Ravindranath V. 2002. Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite. Pharmacogenomics J 2 243-258. 

Most sedative drugs, including narcotics and alcohol, potentiate the sedative effects of benzodiazepines. In addition, medications that inhibit hepatic cytochrome P450 (CYP) 3A3/4 increase blood levels and hence side effects of clonazepam, alprazolam, midazolam, and triazolam. Lorazepam, oxazepam, and temazepam are not dependent on hepatic enzymes for metabolism. Therefore, they are not affected by hepatic disease or the inhibition of hepatic enzymes. 

Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam) Available data from clinical... 

Benzodiazepines [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. 

Alprazolam, a triazolobenzodiazepine, is also extensively metabolized by oxidation and conjugation. Metabolites include a-hydroxyalprazolam, 4-hydroxyalprazolam, and a,4-dihydroxyalpra-zolam. The first two metabolites possess approximately 66 and 19% of the pharmacological activity... 

Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (chlordiazepoxide, alprazolam, diazepam) or nitroreduction (nitrazepam) (334). Oral contraceptives inhibit enzyme activity and reduce the clearances of these drugs. There is nevertheless no evidence that these interactions are of clinical importance. For other benzodiazepines that undergo oxidative metabolism, such as bromazepam and clotiazepam, no change has ever been found in oral contraceptive users. 

Alprazolam (Xanax), lorazepam (Ativan), and oxazepam (Serax) are metabolized and cleared from the body more quickly than the other members of this family, and are therefore more likely to produce withdrawal symptoms when they are discontinued. These three drugs, however, are less likely to produce side effects such as impaired coordination, concentration, and memory and muscular weakness or sedation. 

Alprazolam, 269, a popular sedative/hypnotic agent and benzodiazepine receptor agonist, has been labelled257 with 11C in metabolically stable position in reaction of the amidrazone, 7-chloro-5-phenyl-3//-l,4-benzodiazepine-2-yl hydrazone, 270, with 1-[ Cjacetyl chloride followed by pyrolysis of the resulting 1-acetylhydrazone 271. Compound 269 has been obtained in 43-65% yield during 40-55 min at specific activity 0.93-2.18 Ci /miol-1, and used for metabolism and tissue distribution studies257 (equation 107). 

SSRIs and the benzodiazepine alprazolam are often used to treat panic disorder. Pharmacokinetic reactions between them could therefore be important. Alprazolam is metabolized by CYP3A4, which fluvoxamine inhibits (SEDA-22, 13). In 23 out-patients (11 men, 12 women, mean age 39 years) who took alprazolam both as monotherapy (mean dose 1.0 mg/day) and in combination with fluvoxamine (mean dose 34 mg/day), fluvoxamine increased plasma alprazolam concentrations by 58% (97). This was not associated with increased sleepiness, measured by a subjective rating scale, but objective measures of psychomotor function were not carried out and these could have been impaired by raised alprazolam concentrations. 

Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T. Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol 2003 58 829-33. 

The effects of venlafaxine on the pharmacokinetics of alprazolam have been investigated in 16 healthy volunteers. Steady-state venlafaxine 75 mg bd did not inhibit CYP3A4 metabolism of a single dose of alprazolam 2 mg (33). 

---