Drug metabolism, pharmacokinetic saturation

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Two distinct bases for these types of effects may be distinguished pharmacokinetic and pharmacodynamic. Pharmacokinetic-based toxic effects are due to an increase in the concentration of the compound or active metabolite at the target site. This may be due to an increase in the dose, altered metabolism or saturation of elimination processes for example. An example is the increased hypotensive effect of debrisoquine in poor metabolizers where there is a genetic basis for a reduction in metabolic clearance of the drug (see Chapter 5). 

Karlsson, M.O. Molnar, V., Freijs, A., Nygren, P., Berghm, J., and Larson, R. Pharmacokinetic models for the saturable distribution of paclitaxel. Drug Metabolism and Disposition 1997 27 1220-1223. 

The potential for the metabolites that are formed to have the same masses as other parent compounds is another factor that limits the number of compounds that may be included in the cassette, as does the potential for drug-drug interactions [35]. Other limitations are the total dose that can be administered without saturating important pathways of metabolism or distribution, and the solubility of the compounds in the dosing formulation. However, there is a balance to be achieved as, if the dose of each component given is very low, it is likely that the analytical method will not have sufficient sensitivity to provide an accurate assessment of the pharmacokinetics. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Metabolism/Excretion - There are 2 genetically determined patterns of propafenone metabolism. In more than 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life of 2 to 10 hours. These patients metabolize propafenone into two active metabolites 5-hydroxypropafenone and N-depropylpropafenone. They both are usually present in concentrations less than 20% of propafenone. The saturable hydroxylation pathway is responsible for the nonlinear pharmacokinetic disposition. 

This equation has a concentration term, C0, indicating that the half-life is variable and dependent on drug concentration. Changes in pharmacokinetic parameters that occur as a function of dose or drug concentration are referred to as nonlinear pharmacokinetic processes. Nonlinearity is usually due to saturation of protein binding, hepatic metabolism, or active renal transport of the drug.3... 

Once-daily administration of modified-release formulation of fluvastatin 80-320 mg/day was generally safe and well tolerated in 40 patients with primary hypercholesterolemia over 13 days (7). However, fluvastatin 640 mg in this formulation was not well tolerated six of seven patients had adverse events, including diarrhea, headache, and rises in serum transaminases. In addition, the pharmacokinetics of fluvastatin were non-linear at this dose, possibly because of saturation of first-pass metabolism, causing higher than expected serum drug concentrations. 

Pharmacokinetics and absorption of the drug should be linear. If the pharmacokinetic processes are dependent on the fraction of dose reaching the systemic blood flow (or of the dose administered) or on the rate of absorption, comparison between formulation and simulation cannot be made. This non-linearity may be owing to saturable absorption processes (active absorption), induction or inhibition of the metabolism, the first past effect, which is rate/absorption dependent, etc. Those points must be studied before any attempt to establish an IVIVC. 

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