Pharmacokinetic interactions displacement

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

The pharmacokinetic interaction of phenytoin with valproate is complicated (78-80). Initially, the total serum phenytoin concentration falls, because valproate displaces phenytoin from protein binding sites and so the unbound fraction increases, with a consequent increase in clearance. Because of the change in unbound fraction the total plasma concentration effect curve is shifted to the left, and a lower total concentration is as effective as the total phenytoin concentration was in the absence of valproate. However, valproate also inhibits the metabolism of phenytoin and so the serum phenytoin concentration then starts to rise and there is a risk of toxicity. 

Enantiomeric competition for protein binding has also been reported for flurbiprofen enantiomers in rats, with displacement of R-flurbiprofen by its antipode from plasma proteins [268]. Jamali et al. [246] postulated that the interaction between enantiomers of flurbiprofen at protein binding level may explain the increase in the clearance of R-flurbiprofen. However, a more recently published study indicates that the extent of pharmacokinetic interaction between flurbiprofen enantiomers is not significant in humans [269]. 

MacKichan, J.J. (1989) Protein binding drug displacement interactions—fact or fiction Clin Pharmacokinet 16 65-73. 

Bepridil has been the subject of a brief general review (1) and its pharmacokinetics have been specifically reviewed (2). Although it is highly protein-bound, bepridil does not take part in protein-binding displacement interactions (2). 

Characterizing a drug s circadian pharmacokinetics and pharmacodynamics can enable investigators to temporally target the administration time and intensity to maximize patient response and minimize patient toxicity. In these models, the rhythmic displacement in the effect curve is caused by the underlying PK circadian changes in clearance, not any PD interaction. Flence, a direct PD model can stiU be used to model the PD interaction. 

There s also a pharmacokinetic way to analyze the likely outcome of binding displacement interactions on pharmacodynamic outcomes. Steady-state unbound plasma concentrations can be defined in terms of a drug s clearance (CL), the fraction of drug absorbed (F), the dose (D), and the dosing interval, t. 

At a fundamental level, a determination must be made whether a biological mechanism for an interaction exists. The most common pharmacokinetic mechanisms include metabolic inhibition or induction, protein binding displacement, and interference with absorption. Potential pharmacodynamic synergy or antagonism must also be considered. Interactions must be considered from the perspective of... 

Example calculation of changes in pharmacokinetic parameters after a plasma protein-binding displacement interaction... 

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