Pharmacokinetics fluoxetine

Harvey AT, Preskorn SH. Fluoxetine pharmacokinetics and effect on CYP2C19 in young and elderly volunteers. J Clin Psychopharmacol 2000 (in press). 

Piergies AA, Sweet J, Johnson M, Roth-Schechter BF, Allard S. The effect of co-administra-tion of zolpidem with fluoxetine pharmacokinetics and pharmacodynamics. Int JClin Pharmacol Ther (1996) 34,178-83. 

Alosetron had no clinically significant effect on fluoxetine pharmacokinetics in healthy subjects. 

It is perhaps not surprising that, even after taking into account pharmacokinetic differences between these drugs, the therapeutic doses of the SSRIs do not parallel their Ki for inhibition of 5-HT reuptake. For instance, citalopram is about a thousand times more selective than fluoxetine for inhibition of 5-HT uptake, and yet their clinically effective doses are similar. In short, not only is their selectivity for the 5-HT transporter in vitro a poor predictor of their efficacy in vivo but it has to be questioned whether any of these compounds actually work by blocking 5-HT uptake alone. 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

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. 

Preskorn S (1994) Targeted pharmacotherapy in depression management comparative pharmacokinetics of fluoxetine, paroxetine and sertraline. Int Clin Psychopharmacol 9(Suppl3) 13-19... 

L. T. Kerner, B. Cohen, P.F. Renshaw, A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine A 19-F MRS study. Neuropsychopharmacology 30 (2005) 1576-1583. 

Fraser, A.G. (1997) Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet 33 79—90. Friedman, E.H. (1994) Re bradycardia and somnolence after adding fluoxetine to pimozide regimen. Can/ Psychiatry 39 634. 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

Preskorn, S.H., Alderman, J., et al. (1994) Pharmacokinetics of de-sipramine coadministered with sertraline or fluoxetine. / Clin Psy-chopharmacol 14 90-98. 

Wilens, TE. (2001) Pharmacokinetics of fluoxetine pediatric patients (personal communication). 

Wilens T, Cohen LG, Beiderman J, Abrams A, neft D, Melnick K, Kurtz D, and Sinha V (2000, poster). Pharmacokinetics of fluoxetine in pediatric patients. Scientific Proceedings of the 47th Annual Meeting of The American Academy of Child And Adolescent Psychiatry. October 24-29, 2000). New York, NY. 

To put this in perspective, the mean half-live of norfluoxetine is 20 days in a physically healthy older patient. That means it will take 100 days to achieve C ss oi ce fluoxetine has been started and 100 days to clear 97% of this active metabolite once the parent compound has been stopped. These times may be even longer at higher doses because fluoxetine has nonlinear pharmacokinetics over its recommended dosing range (i.e., autoinhibition). 

Preskorn SH, Alderman J, Chung M, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J Clin Psychopharmacol 1994 14 90-98. 

Schmider J, von Moltke LL, Shader Rl, et al. Extrapolating in vitro data on drug metabolism to in vivo pharmacokinetics evaluation of the pharmacokinetic interaction between amitriptyline and fluoxetine. Drug Metab Rev 1999 31 545-560. 

Fluvoxamine, fluoxetine, and paroxetine have nonlinear pharmacokinetics, which means that dose increases lead to disproportionately greater increases in plasma drug levels (25). In contrast, citalopram and sertraline have linear pharmacokinetics. For these reasons, dose increases with fluvoxamine, fluoxetine, and paroxetine can lead to greater than proportional increases in concentration-dependent effects such as serotonin-mediated adverse effects (e.g., nausea) and inhibition of specific CYP enzymes. 

The dearth of information on the metabolism of bupropion may initially seem surprising however, this drug is one of the oldest of the newer antidepressants, having entered clinical trials in the mid-1970 s and having been approved before fluoxetine ( 308, 314, 315). Ironically, its marketing was delayed after its approval because of the risk of seizures, which, in turn, is almost undoubtedly a consequence of its complicated pharmacokinetics ( 163). 

In comparison with TCAs, SSRIs cause fewer pharmacodynamic drug-drug interactions but some (i.e., fluvoxamine, fluoxetine, paroxetine) cause more CYP enzyme mediated pharmacokinetic drug-drug interactions. Unlike TCAs, SSRIs do not potentiate alcohol and perhaps even slightly antagonize its acute CNS effects. Nevertheless, there are some important adverse interactions. 

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. 

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