Drug interactions direct inhibition

Direct inhibition of P450 enzymatic activity is the most common reason for drug-drug interactions. 

Fig. 3. Possible interactions between PKC and MDRl-mediated drug resistance. Activation of PKC might activate the drug efflux by phosphorylation of PGP (A), induce or activate proteins which modulate PGP (B, Castro et al., 1999), or induce the transcription and translation of MDRl-mRNA (C). Inhibitors of PKC might prevent phosphorylation of PGP leading to a decrease the drug efflux (D). inhibit the efflux of drugs by direct interaction with the drug binding site(s) or the ATP-binding sites of PGP (E), or prevent the expression of MDRl-mRNA (F)...

Direct evidence that irreversible inhibition is the principle mechanism underlying in vivo drug-drug interactions (DDIs) is often lacking because of the requirement for either direct tissue sampling to reveal inactivated enzyme or in vivo inhibition of activity after drug is essentially eliminated from the body. Nevertheless the steady-state plasma concentrations of several clinically important CYP inhibitors are well below the in vitro estimated competitive inhibition constant, Kv This suggests that competitive inhibition is unlikely to occur in vivo, yet these compounds inhibit CYP activity in a time and concentration-dependant manner when cDNA-expressed CYPs or HLMs are used as an enzyme... 

Inhibitory drug interactions generally fall into two categories. The first involves direct inhibition of the metabolism of one drug by the other. Direct inhibition may exhibit Michaelis-Menten kinetic characteristics... 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

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