Victim drugs

If one assumes that an inhibitor or inactivator, selective for an enzyme in question, can be dosed in such a manner so as to completely abolish the activity of an enzyme in vivo, then a clinical DDI study using that inhibitor can be used to estimate for that enzyme for the victim drug. 

Figure 1 The effect of fractional metabolism by CYP,/m(CYp), on the theoretical increase in exposure to a victim drug with increasing inhibition by a perpetrator drug based on [I /Ki values. Abbreviation CYP, cytochrome P450.

Figure 1 Schematic representation of the mechanism of pharmacokinetic drug interactions. Plasma concentrations of the victim drug are determined by its dosing rate and metabolic clearance. Plasma levels, in turn, determine drug concentrations at the receptor site and ultimately its pharmacodynamic effect. A pharmacokinetic drug interaction involves the effect of the perpetrator on the metabolic clearance of the victim. When the perpetrator is an inducer, clearance of the victim is increased, plasma levels are diminished, and pharmacological effect is reduced. Conversely, when the perpetrator is an inhibitor, clearance of the victim is reduced, plasma levels are increased, and pharmacodynamic effect is enhanced.

A pharmacodynamic interaction involves either inhibition or enhancement of the clinical effects of the victim drug as a consequence of similar or identical end-organ actions. Examples are the increase or decrease of the sedative-hypnotic actions of benzodiazepine agonist drugs due to coadministration of ethanol or... 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

Predicting DDIs When Victim Drugs Are Processed Both by CYPs and PgP, and When Perpetrators Inhibit Both 319... 

By what mechanisms might a perpetrator alter the AUG of a victim drug Simply put, a perpetrator might be expected to increase the AUC of a victim drug by ... 

Blocking the efflux of the victim drug from hepa-tocytes into the bile... 

Slowing renal secretion of the victim drug into the urine... 

Decreasing the protein or tissue binding of the victim drug... 

Contrariwise, a perpetrator could be expected to decrease the AUC of a victim drug by interfering with its absorption or bioavailability, accelerating its metabolism in the intestine or liver, or accelerating its efflux from intestinal cells into the lumen of the intestine or... 

Accounting for the Fraction of Drug Metabolized by a Given GYP Enzyme How much of a victim drug must be metabolized by an enzyme, before enzyme inhibition by a perpetrator is likely to be clinically significant Benchmarks have been set as low as 30%, but a good case can be made for 50%. Por a drug that is cleared in part by metabolism via a GYP enzyme, its clearance in the presence of an inhibitor (perpetrator) of that enzyme can be defined as follows ... 

Thus, only if fmcYpvrere 0.5 would the AUG ratio double by GYP inhibition. However, as described earlier, the extent of clearance inhibition associated with enzyme inhibition actually depends upon the Ki value for the perpetrator. If a victim drug is metabolized by a single GYP enzyme, and if metabolism accounts for >50% of the victim drug s total clearance, then the AUG ratio arising from inhibition of that enzyme by a perpetrator is given by the Rowland-Matin equation ... 

If a victim drug (i.e., substrate) is subject to multiple metabolic pathways accounting for more than 50% of the total clearance of the victim drug, and if a perpetrator (inhibitor) affects those enzymes in quantitatively different ways, another layer of complexity is added to the estimation of the AUG ratio from [7]/A) data. If, say, two pathways are subject to inhibition by a particular inhibitor, the fraction of victim drug metabolized by each of the two pathways is known, and the K values for the perpetrator on each of the two pathways is known, then the AUG ratio can be described by ... 

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