(E)-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its cerebrospinal fluid level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptylines. Based on this, (E)-10-hydroxynortriptyline was suggested to significantly contribute to antidepressant effects of amitriptyline.Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with clearance difference of up to 10-fold, vary widely between individuals. Variability of the area under the curve in steady state is also high, which makes a slow upward titration of the dose necessary.In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (E)-10-hydroxynortiptyline is about 60% bound. Amitriptyline has an elimination half life of 21 hours, nortriptyline - 23–31 hours, and (E)-10-hydroxynortiptyline - 8–10 hours. Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites. 2% of the unchanged drug is excreted in the urine. Elimination in the feces, apparently, have not been studied. Therapeutic levels of amitriptyline range from 75 to 175 ng/mL (270–631 nM), or 80–250 ng/mL of both amitriptyline and its metabolite nortriptyline. Pharmacogenetics
Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.
Although it is unclear as to how gas formation occurs in emphysematous cystitis, its dependent on whether or not the patient has contributing diseases. Gas formation in diabetic patients diagnosed with Emphysematous cystitis has been determined to occur due to the production of carbon dioxide as a result of the fermentation of the high concentrations of glucose. Gas formation in nondiabetic patients is most likely due to the breaking down of urinary lactulose and tissue proteins. Inflammation caused by infection increases pressure and decreases circulation, which provides the perfect environment for bacteria to produce gas. References
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