Amitriptyline pharmacokinetics

Baumann P, Jonzier Percy M, Koeb L, etal. Amitriptyline pharmacokinetics and clinical response II. Metabolic polymorphism assessed by hydroxylation of debrisoquine and mephenytoin. Int Clin Psychopharmacol 1986 1(2) 102-12. 

Note Derivatization with this reagent sequence in combination with extraction and TLC separation is speciftc for amitriptyline and nortriptyline in the analysis of plasma furthermore its high sensitivity allows its employment in pharmacokinetic studies, e. g. after the oral administration of a single dose of 25 mg amitriptyline. 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

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. 

When a dmg is in its unionised form it will more readily diffuse from the urine to the blood. In an acidic urine, acidic drugs will diffuse back into the blood from the urine. Acidic compounds such as nitrofurantoin are excreted faster when the urinary pH is alkaline. Amfetamine, imipramine and amitriptyline are excreted more rapidly in acidic urine. The control of urinary pH in studies of pharmacokinetics is thus vital. It is difficult, however, to find compounds to use by the oral route for deliberate adjustment of urinary pH. Sodium bicarbonate and ammonium chloride may be used but are unpalatable. Intravenous administration of acidifying salt solutions presents one approach, especially for the forced diuresis of basic dmgs in cases of poisoning. 

Much of the study of interethnic differences in the pharmacokinetics and pharmacodynamics of psychotropic medications has involved TCAs and differences between Asians and Caucasians (Pi et al. 1993a). As with antipsychotics, there are clinical reports that Asians require lower doses of TCAs (Pi and Gray 1998 Pi et al. 1993a). It has also been suggested that Asians show a therapeutic response at lower blood levels of TCAs (Yamashita and Asano 1979), suggesting pharmacodynamic differences. Other studies of prescribing patterns have failed to confirm this and found that the daily doses of amitriptyline, imipramine, doxepin, and nortriptyline prescribed by psychiatrists at 29 medical schools in 9 Asian countries were the same as those used in the United States (Pi et al. 1985). It was also reported that Asians and whites need similar doses of at least 150 mg/day to attain recommended therapeutic blood concentrations (Kinzie et al. 1987). 

Several agents commonly used in the CKD population have been evaluated for interactions with cinacalcet. Coadministration of calcium carbonate or sevelamer did not affect the pharmacokinetics of cinacalcet. Pantoprazole did not alter the pharmacokinetics of cinacalcet HCl, an important finding since pantoprazole alters gastric pH, and the solubility of cinacalcet decreases as the gastric pH rises over 5.5. Coadministration of cinacalcet with warfarin also did not affect the pharmacokinetics of warfarin. Coadministration of cinacalcet and ketoconazole, a strong inhibitor of CYP3A4, resulted in an increase in the area under the curve and maximum concentration of 2.3 and 2.2 times, respectively. Concurrent administration of cinacalcet with amitriptyline increased amitriptyline exposure and nortriptyhne (active metabohte) exposure by approximately 20% in CYP2D6-extensive metabohzers. 

Amitriptylinoxide. S-(I0,Il-Dihydro-5H-diben-zo[a,d]cyclohepten-S-yiidene)-N,N-dimethyl-l-propanamine N-oxide 10,ll-dihydro-N,H-dimethyl-5H-dibenzo[a,d]cyclo-heptene-A -propylamine N-oxide amitriptyline N-oxide Ambivalon Equilibrin. C H NO mol wt 293.41. C 81,87%. H 7.90%, N 4.77%, O 5.45%. Centrally acting metabolite of amitriptyline, q.v. Prepn J. B. Pedersen, Brit, pat. 991,651 corresp to IIS. pat. 3,299,139 (1965, 1967 both to Dumex). Series of articles on pharmacology, pharmacokinetics, metabolism, clinical studies, toxicity studies, terato-logical Studies Arzneimillel-Forsch. 28, 1873-1926 (1978). HPLC determn K. M. Jensen, J. Chromatog. 183, 321... 

Oshima, N. Kotaki, H. Sawada, Y. Iga, T. Tissue distribution of amitriptyline after repeated administration in rats. Drug Metab.Dispos., 1994,22, 21-25 [rat plasma liver kidney lung brain muscle heart extracted nortriptyline clomipramine is IS column temp 35 LOQ 10 n mL pharmacokinetics]... 

Terlinden, R. Borbe, H.O. Determination of amitriptylinoxide and its major metabolites amitriptyline and nortriptyline in plasma by high-performance liquid chromatography. J.Chromatogr., 1986, 382, 372-376 [plasma column temp 45 extracted amitriptylinoxide desipramine (IS) LOQ 10 ng/mL pharmacokinetics dog]... 

Amitriptyline is rapidly absorbed from the Gl tract and from parenteral sites. Its pharmacokinetics are shown in Table 21.9. Amitriptyline and its active metabolite, nortriptyline, are distributed into breast milk. Amitriptyline is primarily (65%) metabolized by N-demethylation by CYP2D6 to nortriptyline and hydroxylation to its -10-hydroxy metabolite. Nortriptyline is pharmacologically active as a secondary amine TCA. Amitriptyline shows approximately equal affinity for 5-HT and NE transporters. 

Dorian P, Sellers EM, Reed KL, Warsh JJ, Hamilton C, Kaplan HL, Fan T. Amitriptyline and ethanol pharmacokinetic and pharmacodynamic interaction. EurJ Clin Pharmacol (1983)... 

No pharmacokinetic interaction normally occurs between risperidone and amitriptyline or mirtazapine, but extrapyramidal reactions have been reported in one patient taking amitriptyline with risperidone. 

A study in 12 schizophrenic patients found that amitriptyline 50 to 100 mg daily had no effect on the serum levels of risperidone 3 mg twice daily. However, a 26-year-old man taking amitriptyline 25 mg daily developed extrapyramidal reactions alter his dosage of risperidone was increased from 2 to 4 mg daily On another occasion extrapyramidal adverse effects developed after risperidone 2 mg daily was added to treatment with amitriptyline 25 mg and fluoxetine 20 mg daily. Both pharmacokinetic and pharmacodynamic reasons for this reaction have been suggested. The cases illustrate that there is the potential for an adverse interaction between these drugs, which should be borne in mind when prescribing both drugs. 

Sommers DK, Snyman JR, van Wyk M, Blom MW, Huang ML, Levron JC. Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients. IntClin Psychopharmacol (1991) 12, 141-5. 

A study in 17 lithium-maintained patients found that tremor increased significantly when amitriptyline 75 to 150 mg daily was added. The greatest increments occurred within approximately 3 weeks of starting the combined treatment, but tremor activity was still significantly greater than baseline after 6 weeks. No patient discontinued treatment because of the increase in tremor. Seizures occurred in a patient on amitriptyline 300 mg daily, 13 days after lithium carbonate 300 mg three times daily was started. After recovery, combined therapy was resumed, but further seizures occurred 10 days later. Her lithium levels were 0.9 mmol/L three days before this second episode. She later took amitriptyline 500 mg daily without adverse effect. Another patient developed neuroleptie malignant syndrome after one week of treatment with lithium carbonate 300 mg and amitriptyline 25 mg, both three times daily. The patient had also received chlorpromazine for one week, just before the lithium-antidepressant therapy was started. No pharmacokinetic interaction was found in 10 therapy-resistant patients with major depression who were given amitriptyline and lithium for 4 weeks. ... 

Only a minor and clinically unimportant change in the pharmacokinetics of amitriptyline occurs in patients given toloxatone. ... 

Dugal R, Caille G, Albert J-M, Cooper SF. Apparent pharmacokinetic interaction of diazepam and amitriptyline in psychiatric patients a pilot study. Curr TherRes (1975) 18,679-87. 

Orlistat appears not to affect the plasma levels of clomipramine or desipramine in patients, or the pharmacokinetics of amitriptyline in healthy subjects. 

A preliminary study in patients who had been taking psychotropic drugs long-term found no clinically relevant changes in plasma levels of clomipramine (3 patients) or desipramine (1 patient) when they were given orlistat over an 8-week period. A study in 20 healthy subjects found that orlistat 120 mg three times daily for 6 days did not affect the pharmacokinetics of amitriptyline 25 mg three times daily. ... 

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. ... 

A number of other reports and studies clearly confirm that marked increases occur in the levels of amitriptyline, " clomipramine, desipramine, " imipramine " and nortriptyline, " accompanied by toxicity, if fluoxetine is added without reducing the dosage of the tricyclic antidepressant. Delirium and seizures have also been described, and a death has been attributed to chronic amitriptyline toxicity caused by fluoxetine. The pharmacokinetics of fluoxetine appear not to be affected by amitriptyline. ... 

Terbinafme markedly increased the AUC of desipramine in a pharmacokinetic study. Case reports describe increases in the serum levels of amitriptyline, desipramine, imipramine and nortriptyline, with associated toxicity, in patients additionally given oral terbinafme. 

Castberg I, Helle J, Aamo TO. Prolonged pharmacokinetic drug intemction between terbinafme and amitriptyline. Ther DrugMonit (2005) 27,680-2. 

Amitriptyline and nortriptyline plasma levels can be increased by sodium valproate and valpromide, but in contrast, an isolated report attributes a paradoxical rise in serum desipramine levels to the withdrawal of valproic acid. Valproate pharmacokinetics may be moderately affected by amitriptyline. Status epilepticus has been attributed to elevated clomipramine levels in a patient taking valproic acid. 

Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR. Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol Ther 996) 60, 48-53. 

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