Venlafaxine pharmacokinetics

Fukuda, T. et al. (2000). The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur. J. Clin. Pharmacol, 56, 175-80. 

Franchini L, Serretti A, Gasperini M, Smeraldi E (1998) Familial concordance of fluvoxamine response as a tool for differentiating mood disorder pedigrees. J Psychiatr Res 32 255-259 Fukuda T, Nishida Y, Zhou Q, Yamamoto I, Kondo S, Azuma J (2000) The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Fur J Clin Pharmacol 56 175-180... 

Troy S, Piergies A, Lucki I, et al. Venlafaxine pharmacokinetics and pharmacodynamics. Clin Neuropharmaco, 1992 15[Suppl 1] 324B. 

Fukuda T, Yamamoto 1. Nishida Y, etal. Effect of the CYP2D6 10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers. Br J Clin Pharmacol 1999 47(4) 450-3. 

Pharmacokinetic parameters of the newer antidepressants are shown in Table 35— 5.9,29 Several antidepressants are not very highly protein bound, and the most notable of these is venlafaxine. The elimination half-lives of nefazodone and... 

Pharmacokinetics Venlafaxine is well absorbed (at least 92%) and extensively metabolized in the liver. ODV is the only major active metabolite. Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Venlafaxine ER provides a slower rate of absorption but the same extent of absorption compared with the immediate-release tablet. 

Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

Ereshefsky L, Dugan D (2000) Review of the pharmacokinetics, pharmacogenetics, and drug interactions potential of antidepressants focus on venlafaxine. Depress Anxiety 12(Suppl l) 30-44... 

W.J., and Chiang, S.T. (1992) Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. / Clin Pharmacol 32 716-724. 

A more common approach in difficult to treat cases would be the combination of clomipramine with a SSRI several reports lend support to this practice (Simeon and Thatte, 1990 Figueroa et al., 1998). In this situation, careful attention to the potential pharmacokinetic interactions discussed above are recommended. Sertraline and citalopram are least likely to elevate tricyclic levels due to less potential GYP interactions. By expert consensus, second- (venlafaxine) and third-line (nefazadone and gabapentin) agents may be used when clinical response is inadequate despite a lack of controlled data. Venlafaxine may be substituted for a more typical SSRI while nefazadone or gabapentin may be added to either clomipramine or a SSRI. The combination of venlafaxine with other SSRIs is not generally recommended as it may increase the risk of a serotonin syndrome. The addition of nefazadone to SSRIs presents a lesser risk. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Although venlafaxine can have more interactions than SSRIs pharmacodynamically, it is comparable with citalopram and sertraline in terms of not causing CYP enzyme mediated pharmacokinetic drug-drug interactions (Table 7-29). Thus, these three antidepressants have a distinct advantage over drugs such as fluoxetine, particularly in patients who are likely to be on other medications in aaaition to their antidepressant. 

Preskorn SH. Pharmacokinetic profile of Effexor (venlafaxine HCI). Poster displayed at the 150th Annual Meeting of the American Psychiatric Association, Philadelphia, May 21,1994. 

The first studies of venlafaxine and nefazodone in both children and adolescents examined pharmacokinetics, safety, and tolerability of these agents ( 35, 36). As expected, the clearance was modestly more rapid in children and adolescents for both of these medications when compared with clearance in adults, but the difference was not sufficient to warrant a significant change in the milligram per kilogram daily dose. These studies should be followed up by appropriately designed efficacy studies. 

The pharmacokinetics of these drugs are similar to those of the tricyclics (Table 30-2). Some may have active metabolites. Trazodone and venlafaxine have short plasma half-lives, which mandates divided doses during the day when beginning treatment, though once-a-day dosing may be possible later. Extended-release forms of bupropion and venlafaxine allow for once-a-day dosing in some patients from the outset. 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Wei Z, Bing-Ren X, Cai-Yun W (2007) Liquid chromatography-mass spectrometry method for the determination of venlafaxine in human plasma and application to a pharmacokinetic study. Biomed Chromatogr 21 266-272... 

Qin F, Li N, Qin T et al (2010) Simultaneous quantification of venlafaxine and O-desmethylvenlafaxine in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. J Chromatogr B Anal Technol Biomed Life Sci 878 689-694... 

Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 2002 63(3) 181-6. 

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). 

Klockowski PM. Effect of venlafaxine on the pharmacokinetics of alprazolam. Psychopharmacol Bull 1998 34(2) 211-9. 

Levin GM, Nelson LA, DeVane CL, Preston SL, Eisele G, Carson SW. A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir. Psychopharmacol Bull 2001 35(2) 62-71. 

Drugs used in the treatment of depression and psychosis can alter the metabolism of terfenadine. When the antidepressant venlafaxine was given to steady state (37.5 mg bd for 3 days and then 75 mg bd for 5 days), the pharmacokinetics of a single dose of terfenadine 120 mg were not altered and there were no changes in the electrocardiogram (13). The authors concluded that cardiotoxicity is unlikely to arise with co-administration of terfenadine and venlafaxine. 

Venlafaxine does not alter the pharmacokinetic disposition of alcohol in healthy volunteers. 

Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of drugs metabolized by CYP3A4 (alprazolam and diazepam). When milnacipran was administered with lorazepam in healthy volunteers, no changes in the pharmacokinetics of any drug were detected. 

Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of caffeine (metabolized by CYP1A2). 

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