*4.3. Inhibitors*

Established inhibitors of CYP1A function include 7-hydroxyflavone and α-naphthoflavone that have been extensively used in vitro [11,14,18,94]. Ketoconazole, a potent inhibitor of CYP3A4 and P-glycoprotein, was also shown to inhibit CYP1A1 in a significant manner [27]. Again, we must state that there are so far insufficient data on the specific inhibitory properties of established CYP1A2 inhibitors on the function of CYP1A1. Considering the similarity in terms of sequence and function, one may hypothesize again a substantial overlap between both isoenzymes. An exception of this conclusion is furafylline, a methylxanthine, which was demonstrated to inhibit specifically CYP1A2 but not CYP1A1 [94]. Thus, it serves as an in vitro tool to distinguish between the metabolic activites of both isoenzymes in microsomal studies.

Typical inhibitors of CYP1A2 are rather small molecules, which are often heterocyclic or halogenated. Drugs resulting in potent competitive but reversible inhibition of CYP1A2 include fluoroquinolones such as ciprofloxacin and enoxacin, selective serotonin reuptake inhibiting (SSRI) antidepressants fluvoxamine and fluoxetin, the azole antimycotics ketoconazole, and clotrimazole, as well as estrogens (oral contraceptives). Some drugs (e.g., amiodarone, carbamazepine, duloxetine, isoniazid, resveratrol, and rofecoxib) were described to be mechanism-based inhibitors [11], i.e., they cause irreversible inhibition of CYP1A enzymes, which requires de novo synthesis of the respective proteins, which, in turn, results in long-lasting enzyme inhibition. Table 4 provides an overview of clinically used drugs that were identified as potent inhibitors of CYP1A. As it can be seen from the given inhibitory potential of each compound as assessed in vitro (Ki or IC50 values), compounds with high inhibition potency, such as ciprofloxacin (Ki, 144 nM for CYP1A2), fluxoxamine (Ki, 11-40 nM for CYP1A2), or ketoconazole (Ki, 40 nM for CYP1A1) are especially expected to cause clinicallyrelevantdrug–druginteractions[27,127,128].


**Table 4.** Overview of clinically relevant drugs with inhibitory properties on CYP1A1/1A2.


**Table 4.** *Cont.*

1 Competitive (reversible) inhibitor; 2 mechanism-based (irreversible) inhibitor; 5-HT, 5-hydroxy tryptamine; COX, cyclooxygenase; HLM, human liver microsomes; IC50, half maximal inhibitory concentration; Ki, inhibition constant; NSAID, nonsteroidal anti-inflammatory drug; SSRI, selective serotonin reuptake inhibitor.
