Pharmacokinetics drug interactions affecting

Pharmacokinetic drug interactions occur where one drug affects the absorption, distribution, metabolism or excretion of the other. Pharmacokinetic drug interactions are harder to predict than pharmacodynamic drug interactions and in many cases, affect different patients differently. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

Antipsychotic pharmacokinetics can be significantly affected by concomitantly administered enzyme inducers or inhibitors. Smoking is a potent inducer of hepatic enzymes and may increase antipsychotic clearance by as much as 50%. The published literature may be consulted for a listing of antipsychotic drug interactions. 

Apart from patient-specific parameters, external factors - most importantly the concomitant uptake of certain other chemicals present in diet, environment and especially other drugs - influence drug actions. Possible effects are manifold and can affect all stages of pharmacokinetic and pharmacodynamic processes in the body. Also direct interaction and inactivation of concomitantly administered substances are possible. Drug-drug interactions via modulation of metabolism present a very hot topic in pharmaceutical research and drug design. 

Factors That Affect Compliance Side Effects, Risk-Benefit Ratio, Drug-Drug Interactions, Pharmacokinetic or Pharmacodynamic Effects, Cost, and Preferences... 

In another study by the same investigators, 10 healthy volunteers were randomized in a two-way, crossover study either to oral lovastatin or to intravenous diltiazem followed by oral lovastatin. Intravenous diltiazem did not significantly affect the pharmacokinetics of lovastatin (oral AUC, Cmax, tmax, or half-life), suggesting that the interaction does not occur systemically and is primarily a first-pass effect (11). Drug interactions with diltiazem may therefore become evident when a patient is changed from intravenous to oral dosing. 

Although when related to a dose the clinical outcome of a drug interaction may appear the same, it is useful to distinguish between pharmacokinetic and pharmacodynamic causes of the interaction. In the former case, the change in response is caused by a change in the concentration of the affected dmg, together perhaps with one or more metabolites. In the latter, there may be no change in pharmacokinetics at all. 

The pharmacokinetics of drug-drug interactions has been described in detail in another chapter (see chap. 1) however, a number of points are worth briefly reiterating in the context of P450. For an inhibition interaction, the affected drug... 

In addition to these fundamental aspects of drug action, the important area of drug interactions will be considered in Chapter 4. Although this subject does not require exhaustive coverage, it is important to appreciate its ramifications early in the study of pharmacotherapeutics since the coincidental administration of drugs can affect their respective pharmacokinetics. In some cases their interaction can be clinically significant. 

It is well known that the response to a drug can differ between diseased and nondiseased individuals. For example, the expression of both pro- and anti-inflammatory mediators changes in many diseases and conditions such as rheumatic diseases, myocardial infarction, angina, aging, and obesity [21]. This may have an impact on toxicity and pharmacokinetics, and in particular, when the drug interacts with these mediators. In addition the pharmacokinetics of a drug can be affected by disease in general, a topic that is discussed later in this chapter. 

---