Pharmacokinetic profile, nonlinear

However when the dose level is increased until the concentration in the body approaches or exceeds the value for any saturable process, then the direct proportionality maintained at lower dose levels will be lost and the relationship of the concentration of the chemical and its metabolites to the dose level will no longer be a constant value. This deviation from a constant relationship between the administered dose level and the concentrations within the body results in a nonlinear pharmacokinetic profile. 

Within this context, the range of dose levels of a chemical causing a transition from a linear to a nonlinear pharmacokinetic profile comprise the pharmacokinetic threshold dose range for the chemical. The change in the relationship between the internal concentration of the toxic entity and the dose level must be taken into account when extrapolating the observed response at dose levels above the pharmacokinetic threshold to the expected response at much lower dose levels. 

The diversity of the SSRIs is evident not only in their chemical structures, but also in their pharmacokinetic profiles. Fluoxetine has an elimination half-fife of 2 to 3 days (4 to 5 days with multiple dosing). The single-dose hah-hfe of norfluoxetine, the active metabolite, is 7 to 9 days. Paroxetine and sertrahne have half-lives of approximately 24 hours. Unlike paroxetine, sertraline has an active metabolite, but the metabohte contributes minimally to the pharmacologic effects. Escitalopram has a half-life of approximately 30 hours. Peak plasma concentrations of citalopram are observed within 2 to 4 hours after dosing, and the elimination half-life is about 30 hours. The SSRIs, with the exception of fluvoxamine, escitalopram, and citalopram, are extensively bound to plasma proteins (94% to 99%). The SSRIs are extensively distributed to the tissues, and aU, with the possible exception of citalopram, may have a nonlinear pattern of drug accumulation with long-term administration. ... 

Linear pharmacokinetics within the investigated rate of delivery (dose/time units) of the drug to the body, i.e., the plasma concentration-time profile, should be identical for different doses after correction for dose. The most common reason for nonlinear pharmacokinetics is dose-dependent first-pass metabolism. This phenomenon does not just occur at high doses, but has also been shown for the slow delivery rates obtained by ER formulations. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

In conclusion, pharmacokinetics is a study of the time course of absorption, distribution, and elimination of a chemical. We use pharmacokinetics as a tool to analyze plasma concentration time profiles after chemical exposure, and it is the derived rates and other parameters that reflect the underlying physiological processes that determine the fate of the chemical. There are numerous software packages available today to accomplish these analyses. The user should, however, be aware of the experimental conditions, the time frame over which the data were collected, and many of the assumptions embedded in the analyses. For example, many of the transport processes described in this chapter may not obey first-order kinetics, and thus may be nonlinear especially at toxicological doses. The reader is advised to consult other texts for more detailed descriptions of these nonlinear interactions and data analyses. 

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