Duloxetine pharmacokinetics

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. 

Lobo ED, Loghin C, Knadler MP et al (2008) Pharmacokinetics of duloxetine in breast milk and plasma of healthy postpartum women. Clin Pharmacokinet 47 103-109... 

Ma N, Zhang BK, Li HD et al (2007) Determination of duloxetine in human plasma via LC/ MS and subsequent application to a pharmacokinetic study in healthy Chinese volunteers. Clin Chim Acta 380 100-105... 

Senthamil Selvan P, Gowda KV, Mandal U et al (2007) Determination of duloxetine in human plasma by liquid chromatography with atmospheric pressure ionization-tandem mass spectrometry and its application to pharmacokinetic study. J Chromatogr B Anal Technol Biomed Life Sci 858 269-275... 

Zhao RK, Cheng G, Tang J et al (2009) Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers a randomized, open-label, single- and multiple-dose study. Clin Ther 31 1022-1036... 

Via CYP4501A2 inhibition, duloxetine could theoretically reduce clearance of theophylline and clozapine however, studies of co-administration with theophylline did not demonstrate significant effects of duloxetine on theophylline pharmacokinetics... 

Duloxetine appears to be fairly well absorbed after oral doses, with peak plasma levels in 6 to 10 hours and linear pharmacokinetics (Table 21.10) (71). The drug is extensively metabolized in the liver to active metabolites, with 72% of an oral dose primarily excreted in the urine as conjugated metabolites and up to 15% appearing in the feces. Its elimination half-life, time to steady-state blood levels, and mean volume of distribution are shown in Table 21.10. 

Lantz RJ, Gillespie TA, Rash TJ, et al. Metabolism, excretion, and pharmacokinetics of duloxetine in healthy human subjects. Drug Metab Dispos 2003 31 1142-11 50. 

Visual hallucinations have been seen in one patient given zolpidem and venlafaxine. No important interaction normally appears to occur between venlafaxine and alprazolam or diazepam. The pharmacokinetics of duloxetine were not affected by lorazepam or temazepam. 

The studies suggest that no special precautions are necessary during the concurrent use of venlafaxine and diazepam or alprazolam, or between duloxetine and lorazepam or temazepam. Similarly, the manufacturer of duloxetine reports that its pharmacokinetics were not affected by lorazepam or temazepam under steady state conditions. ... 

Small D, Loghin C, Lucas R, Knadler MP, Zhang L, Chappell J, Bergstrom R, Callaghan JT. Pharmacokinetic evaluation of combined duloxetine and fluvoxamine dosing in CYP2D6 poor metabolizers. Clin Pharmacol Ther (2005) 77, P37. 

Inducers Population pharmacokinetic studies have shown that smokers have almost 50% lower plasma concentrations of duloxetine, when compared with non-smokers. The clinical significance of this finding is unclear. 

The pharmacokinetic interaction with desipramine is established. Although the clinical relevance of the increased levels has not been assessed, the manufacturer recommends caution if duloxetine is given to patients taking desipramine and other similarly metabolised tricyclics, such as nortriptyline, amitriptyline and imipramine. ... 

In a placebo-controlled, crossover study, 14 healthy subjects received du-loxetine 40 mg twice daily and tolterodine 2 mg twice daily for 5 days. Duloxetine increased the steady-state AUC of tolterodine by 71% and its maximum level by 64%. However, duloxetine had no effect on the pharmacokinetics of 5-hydroxymethyl-tolterodine the active metabolite of tolterodine. ... 

Pharmacokinetics duloxetine has an ehmination half-life of about 12 hours and its pharmacokinetics is dose-proportional over the therapeutic range. Patients may reach steady-state plasma concentrations after dosing for 3 days. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. 

Chappell J, He J, Knadler MP, Mitchell M, Lee D, Lobo E. Effects of duloxetine on the pharmacodynamics and pharmacokinetics of warfarin at steady state in healthy subjects. J Clin Pharmacol 2009 49(12) 1456-66. 

Duloxetine In a steady-state study of once-daily warfarin and once-daUy duloxetine in 60 healthy subjects with a stable INR of 1.5-2.0, duloxetine had no clinically or statistically significant effects on the pharma-codjmamics or pharmacokinetics of warfarin [38. ... 

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