Pharmacokinetics, origin

Alloul K, Whalley DG, Shutway F, Ebrahim Z, Varin F. Pharmacokinetic origin of car-bamazepine-induced resistance to vecuronium neuromuscular blockade in anestiietized patients. Anesthesiology ( 996) 84,330-9. 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

Pharmacodynamic tolerance to barbiturates develops over weeks to months, whereas pharmacokinetic tolerance occurs in a period of days. At maximum tolerance, the dosage of a barbiturate may be six times the original dosage. 

Pharmacokinetics emerged as a discipline in the 1960s with its foundation in compartmental modeling, although earlier origins of pharmacokinetics can be traced [1], Mammillary compartmental models provided the framework for phar-... 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

Satellite pharmacokinetic or special study groups Deviations from original study protocol Statistical methods Observations and times Clinical signs Body weights Food consumption Flematology Clinical chemistry Organ weights... 

The study of ADME had its origins in pharmacology, the science of drugs. Because these processes involve rates of different types, this area of study came to be called pharmacokinetics The combined effects of these pharmacokinetic processes determine the concentration a particular chemical (the chemical entering the body or one or more of its metabolites) will achieve in various tissues and cells of the... 

A simple example might make this clearer. Suppose it were known that a 100 mg dose of chemical Z produced an extra 10% incidence of liver tumors in rats. Suppose further that we studied the pharmacokinetics of compound Z and discovered that, at the same 100 mg dose, 10 mg of the carcinogenic metabolite of Z was present in the liver. The usual regulatory default would instruct us to select the 100 mg dose as the point-of-departure for low dose extrapolation, and to draw a straight line to the origin, as in Figure 8.1. We are then further instructed to estimate the upper bound on risk at whatever dose humans are exposed to - let us say 1 mg. If the extra risk is 10% at 100 mg, then under the simple linear no-threshold model the extra risk at 1 mg should be 10% 100 = 0.1% (an extra risk of... 

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