Clinical Pharmacology and Therapeutics. Группа авторов
significant induction in humans when used at therapeutic dose levels. For practical purposes, anticonvulsants (carbamazepine, phenytoin) and rifampicin are the most potent enzyme inducers in clinical use and have produced numerous clinically significant drug interactions, related primarily to increases in the metabolism of CYP2C9, CYP2C19 and CYP3A4 substrates (including, for example, oestrogen and progesterone, the constituents of a combined oral contraceptive pill). Enzyme induction is not, however, limited to administration of prescription drugs. St John's wort, a herbal remedy, can also cause enzyme induction as can cigarette smoking (induction of CYP1A2 substrates, e.g. theophylline) and ethanol (induction of CYP2E1 but unlikely to be clinically relevant).
Enzyme induction produces clinical changes over days or weeks, but the effects of enzyme inhibition are usually observed immediately. In most circumstances, these changes are manifest as:
Therapeutic failure resulting from induction
Adverse effects resulting from inhibition
Clinical relevance occurs when drug therapy needs to be altered to avoid the consequences of the drug interaction and this is most common and most serious in compounds that have a narrow therapeutic index.
A 58‐year‐old man with chronic obstructive pulmonary disease is admitted to hospital with an infective exacerbation. He is on three different inhalers and additionally takes simvastatin for hypercholesterolaemia. He is allergic to penicillin. The admitting doctor prescribes nebulised salbutamol, prednisolone and clarithromycin along with the patient's usual medications. The next day the patient complains of general aches and pains. Could this be due to a drug interaction?
Inhibition
Concurrently administered drugs can also lead to inhibition of enzyme activity, with many P450 inhibitors showing considerable isoform selectivity. Some of the most clinically relevant inhibitors are listed in Table 1.1, together with the isoform inhibited. In some cases this can lead to potentially dangerous adverse events, e.g. ketoconazole decreases the metabolism of the CYP3A4 substrate, terfenadine, leading to QT interval prolongation and torsades de pointes.
Table 1.1 P450 inhibitors involved in drug interactions.
| Major human P450s | Typical inhibitors |
|---|---|
| CYP1A2 | Furafylline, fluvoxamine, ciprofloxacin |
| CYP2C9 | Fluconazole, ketoconazole, sulfaphenazole |
| CYP2C19 | Omeprazole, ketoconazole, cimetidine |
| CYP2D6 | Quinidine, fluoxetine, ritonavir |
| CYP2E1 | Disulfiram |
| CYP3A4 | Ketoconazole, itraconazole, ritonavir, clarithromycin, diltiazem |
As with induction, P450 inhibition is not limited to drug administration. Grapefruit juice is an inhibitor of CYP3A4 activity and produces clinically significant interactions with a number of drugs, including midazolam, simvastatin and terfenadine. This type of information, together with some knowledge of the enzymes involved in a particular drug's clearance, makes it much easier to understand and predict drug interactions.
Clearly, pronounced enzyme inhibition, which may result in plasma concentrations of the inhibited drug being many times higher than intended, can be a major safety issue. For example, co‐administration of ketoconazole or ritonavir with the hypnotic drug midazolam increases the midazolam plasma exposure (AUC – area under the curve) by 15–20 times, a situation which should be avoided.
Genetic factors in metabolism
The rate at which healthy people metabolise drugs is variable. Although part of this variability is a consequence of environmental factors, including the influence of inducers and inhibitors, the main factor contributing to interindividual variability in metabolism is the underlying genetic basis of the drug‐metabolising enzymes. Although there is probably a genetic component in the control of most P450 enzymes, some enzymes (e.g. CYP2C19 and CYP2D6) actually show genetic polymorphism. This results in distinct subpopulations of poor and extensive metabolisers, where the poor metabolisers are deficient in that particular enzyme. There are a number of enzymes under polymorphic control and some clinically important examples are shown in Table 1.2. As with enzyme inhibition, genetic polymorphism is primarily a concern for drugs that have a narrow therapeutic index and that are metabolised largely by a single polymorphic enzyme. In such cases, the phenotype of the patient should be determined and lower doses of the drug used, or alternative therapy should be considered.
Table 1.2 Major enzymes displaying genetic polymorphism.
| Enzyme | Typical substrates | Characteristics |
|---|---|---|
| CYP2C19 | (S)‐Mephenytoin, diazepam, omeprazole | About 2–5% of white people are poor metabolisers, but 18–23% of Japanese people have this phenotype |
| CYP2D6 | Propafenone, flecainamide, desipramine | About 7% of white people are poor metabolisers, but this frequency is only about 2% in black Americans and <1% in Japanese/Chinese |
| N‐Acetyl‐transferase | Hydralazine, sulphonamides, isoniazid, procainamide | About 50% of white people are slow acetylators |
Renal excretion
Three processes are implicated in renal excretion of drugs:
1 Glomerular filtration: This is the most common route of renal elimination. The free drug is cleared by filtration and the protein‐bound drug remains in the circulation where some of it dissociates to restore equilibrium.
2 Active secretion in the proximal tubule: Both weak acids and weak bases have specific secretory sites in proximal tubular cells. Penicillins are eliminated by this route, as is about 60% of procainamide.
3 Passive reabsorption in the distal tubule: This occurs only with un‐ionised, i.e. lipid‐soluble, drugs. Urine pH determines whether or not weak acids and bases are reabsorbed, which in turn determines the degree of ionisation.
If renal function is impaired, for example, by disease or old age, then the clearance of drugs that normally undergo renal excretion is decreased. This is discussed in more detail later in this section.
Clinical pharmacokinetics: dosage individualisation