Induction and drug development.
Enzyme induction is an undesirable drug interaction, effecting the efficacy of co-administered drugs, rather than safety. The number of clinically used drugs which induce P-450 enzymes is, in fact, quite limited. However, in certain disease areas (AIDS, epilepsy) many of the drugs used, whether for primary or secondary indications, have the potential for enzyme induction. Induction is often seen pre-clinically, due to the elevated dose levels used, but this potential rarely transfers to the clinical situation. Some screening of induction potential can be conducted by the use of human hepatocytes, but supply and variable response limits their use. Robust and routine screens for enzyme induction are being developed based on nuclear receptors. However, whilst genuine structure activity relationships may emerge, with these new technologies, none is evident from the clinical information other than in general structures are diverse but most are lipophilic as defined by a positive calculated LogP value. A critical factor in P-450 induction in the clinic, based on the known drugs, is the question of dose size. The major inducible form of P-450 in man is CYP3A4. The drugs that induce CYP3A4 are given in high doses. In contrast to these amounts, many clinically used drugs, which are non-inducers are effective at doses up two orders of magnitude lower. As a first rule for drug discovery/development programmes it seems prudent to obey the "Golden Rules" of drug design: "Ensure moderate daily dose size by having chosen a viable mechanism and then increase potency against the target whilst optimising pharmacokinetics". This approach is exemplified by the antidiabetic compound troglitzone, a clinical CYP3A4 inducer which has a clinical dose of 200-600 mg and rosiglitazone a more potent analogue dose (2-12 mg) which is devoid of CYP3A4 induction in the clinic.
Smith
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Department of Drug Metabolism, Pfizer Central Research, Kent CT13 9NJ, Sandwich, UK.
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D015195:Drug Design; D004790:Enzyme Induction; D006801:Humans; D008099:Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010599:Pharmacokinetics; D010600:Pharmacology; D013329:Structure-Activity Relationship
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human