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some drugs is that they either inhibit or induce one or more of the cytochrome P450s

(Table 18.1). Inhibition means that the intrinsic clearance of the drug and that of other

concomitantly administered drugs is impaired and this may have toxicological con-

sequences whilst enzyme induction results either in increased clearance of the drug

that may render its therapy ineffective and/or in the production of toxic metabolites.

18.1.5 Desirable properties of a new drug

From the foregoing discussion it is evident that the drug discovery and development

processes must lead to a drug that meets a number of criteria:

• Chemical structure: It must possess structural features that allow it to specifically
  interact with and bind to the target protein. To this end it must possess flexibility
  and hydrogen binding potential and be of an appropriate molecular size.


• Physical properties: It must possess some aqueous solubility and adequate
  lipophilicity to allow it to cross membranes to access the target site. Linked to these
  properties, its pKamust be such that it existsin vivopredominantly in the unionised
  state.


• Pharmacological properties: It must have acceptable potency, efficacy, selectivity and
  effectiveness for receptor agonists or binding properties for enzyme inhibitors or
  receptor antagonists. It must also fill an unmet clinical niche. The chemical structure
  and pharmacological properties must be novel to allow patent protection.

Table 18.1Action of some drugs on the major human cytochrome P450 isoforms

P450 isoform Substrate Inhibitor Inducer

CYP1A2 Imipramine, oestradiol,
paracetamol, verapramil,
propranolol

Fluvoxamine,acimetidine,

ciprofloxacin

Omeprazole,

cigarette smoke

CYP2C9 Fluvastatin, ibuprofen,
phenytoin, amitriptyline,
tamoxifen

Fluconazole,afluvastatin,

lovastatin, sulphaphenazole,

phenylbutazone

Rifampicin,

secobarbital

CYP2C19 Diazepam, propranolol,
amitriptyline, omeprazole,
lansoprazole

Lansoprazole, omeprazole,

cimetidine

Carbamazepine,

rifampacin,

prednisone

CYP2D6, Amitriptyline, imipramine,
propranolol

Quinidine,abupropion,a

cimetidine, ranitidine

Rifampicin,

dexamethazone

CYP2E1 Paracetamol, theophylline,
ethanol

Cimetidine, disulfiram Ethanol

CYP3A4 Indinavir, diazepam,
lansoprazole, saquinavir,
lovastatin

Ketoconazole, indinavir,a

nelfinavir,aritonavira

Carbamazepine,

nevirapine,

phenytoin

Note:aStrong inhibitors that cause at least 80% decrease in clearance.

717 18.1 Human disease and drug therapy