Types of inducer
There are several broad groups of drugs and chemicals capable of inducing hepatic metabolism: these include:
• Anticonvulsants, mainly the older established drugs, such as phenytoin, car-bamazepine and phenobarbitone. Topiramate and oxcarbazepine are weaker inducers. These drugs induce many CYP isoforms, including CYPA2, CYP2C8/9, CYP2C19 and CYP3A4/5.
• Steroids, such as dexamethasone, prednisolone and various glucocorticoids, induce CYP3A4/5.
• Polycyclic aromatic hydrocarbons (PAHs); these are found in atmospheric pollution, cigarette smoke, industrial solvents and barbecued meat. They also contaminate foodstuffs and watercourses (particularly dioxins and polycyclic chlorinated biphenyls). These compounds induce the normally non-constitutive CYP1A1 in the liver, as well as CYP1A2, which specializes in polycyclic aromatic amines. Induction of CYP1A1 is also very strong in the lungs in smokers and is a standard marker for heavy tobacco use.
• Antibiotics, such as the rifamycins (rifampicin, rifabutin, rifapentin) and griseofulvin, induce most CYPs including CYP1A2, CYP2C9, CYP2C19 CYP2B6 and CYP3A4. Flucloxacillin is believed to induce CYP3A4/5. The azole CYP inhibitor clotrimazole, is actually an inducer of CYP3A4, although this is not clinically relevant due to very low absorption from an oral dose and the usual application is topical, with virtually zero systemic absorption.
• Recreational agents’ nicotine and PAHs in tobacco products are known inducers of CYP1A2, actually causing plasma levels of the SSRI fluvoxamine to be around half those of non- smokers, Clozapine and warfarin clearance may also be accelerated. Heavy alcohol consumption will induce CYP2E1, which is relevant to chlorzoxazone.
• Herbal remedies; although more research must be conducted into the various herbs on the market, St John’s Wort is the most clinically relevant and investigated herbal inducer (CYP3A4/5).
• Protease inhibitors: agents such as ritonavir and nelfinavir are potent inducers of CYP3A4, but CYP3A5 is induced much less. Paradoxically, ritonavir in particular is a powerful inhibitor of these CYPs.
• Miscellaneous inducers: the atypical stimulant modafinil, used by narcoleptics and some helicopter pilots, is a mild CYP3A4 inducer (greater than 400mg/day), but inhibits CYP2C19. The non-nucleotide reverse transcriptase inhibitors nevirapine and efavirenz induce CYP3A4 and CYP2B6 in a mild to moderate fashion.
Common features of inducers and clinical significance
A new drug is generally regarded as an inducer if it produces a change in drug clearance which is equal to or greater than 40 per cent of an established potent inducer, usually taken as rifampicin. Looking at the structures of the strongest hepatic enzyme inducers there are apparently few common features. These chemicals range in size from very small and water- soluble (ethanol) to very large and lipophilic (PAHs, rifampicin-related agents). However, inducers are usually (but not always) lipophilic, contain aromatic groups and consequently, if they were not oxidized, they would be very persistent in living systems. CYP enzymes have evolved to oxidize this very type of agent; indeed, an elaborate and very effective system has also evolved to modulate the degree of CYP oxidation of these agents, so it is clear that living systems regard inducers as a particular threat among lipophilic agents in general.
The process of induction is dynamic and closely controlled. The adaptive increase is constantly matched to the level of exposure to the drug, from very minor almost undetectable increases in CYP protein synthesis, all the way to a maximum enzyme synthesis that leads to the clearance of grammes of a chemical per day. Once exposure to the drug or toxin ceases, the adaptive increase in metabolizing capacity will subside gradually to the previous low level, usually within a time period of a few days. This varies according to the individual and the drug. Studies with smokers have shown than their enzyme induction subsides in two to four weeks, whilst rifampicin and anticonvulsant induction can subside at similar or slightly quicker timescales.
Estimating the comparative potencies of various commonly used inducing drugs is complicated by inter–ndividual and ethnic differences. However, predictions based on many clinical studies show rifampicin as the most powerful inducer, followed by phenytoin at around 60-70 per cent of rifampicin’s effect, whilst carbamazepine and phenobar-bitone’s potencies lie around the 40 per cent level. Many other drugs, toxins and over the counter herbal remedies also exert inductive effects within this range, although these have not been as well documented. It is important to note that clinically, there may be some reduction in plasma levels caused by one inducer on another drug, but it may or may not be significant enough to lead to the drug falling out of the therapeutic window. Rifampicin, phenytoin, carbamazepine or phenobarbitone are almost always capable of reducing a coadministered drug’s plasma levels by more than half. Hence, when a patient has spent at least two or three weeks on a regimen containing one or other of these drugs, careful consideration should be given to the appropriate dosage of an additional drug to ensure adequate systemic exposure.
