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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.