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The compartmental model analysis by use of simultaneous curve fitting was carried out to ascertain the pharmacokinetic relationship between amitriptyline (AMT) and nortriptyline (NRT) in the serum and brain after acute or chronic oral administration of AMT. The estimated F value, a fraction of dose reached at systemic circulation, and the MD value, a fraction metabolized to NRT, were 0.044 and 0.020, respectively, after acute administration, indicating first-pass metabolism of AMT. The estimated parameters kin and kout, the transfer rate constants to and from the brain, showed no marked difference between AMT and NRT. These findings indicate equivalent ability of AMT and NRT to penetrate into the brain. The area under the concentration curve (AUC) values of AMT and NRT in the serum increased 1.4 and 8.2 times, respectively, with the increase of NRT being greater after chronic administration. The MD value was increased from 0.020 to 0.096, whereas the estimated F value showed no marked change. These results indicate the enhanced first-pass metabolism. The estimated transfer rate constants kin and kout of AMT were close to those of NRT. In addition, the transfer rate constants after chronic administration were similar to those after acute administration, indicating no marked change in penetration into the brain by multiple dosing.

journal of pharmacobio-dynamics

Pharmacokinetic Analysis of Amitriptyline and Its Demethylated Metabolite in Serum and Brain of Rats after Acute and Chronic Oral Administration of Amitrip-tyline.