*4.2. Substrates*

Under the consideration that CYP1A1 is markedly lower expressed in the human liver than CYP1A2 and is also considered to be of extrahepatic relevance, its impact on the metabolic clearance of drugs was formerly assumed to be negligible [10,11]. In contrast to this conclusion, recent studies have clearly verified CYP1A1 protein abundance in human intestine and liver, which challenges the former paradigm of the pharmacokinetically irrelevant CYP1A1 [18,23,30]. Moreover, 15–20 years ago, several studies convincingly demonstrated high metabolic CYP1A1 activity of intestinal and hepatic microsomal fractions [14,27,122]. Associated to this, riociguat (guanylate cyclase stimulator used for the treatment of pulmonary hypertension) and granisetron (5-HT3 receptor antagonist for the treatment of nausea and vomiting following chemotherapy or radiotherapy) were shown to be highly and specifically biotransformed by CYP1A1 [18,122]. In addition, the tyrosine kinase inhibitors axitinib, erlotinib, gefitinib, and ningetinib as well as the toll-like receptor agonist imiquimod and conivaptan (inhibitor of the antidiuretic hormone) have been reported as substrates of CYP1A1 [18,123,124]. Thus, one has to conclude that CYP1A1 should be considered as an additional potentially relevant clearance pathway for some drugs. However, in the past, the metabolic stability of a drug was in most cases studied by using human liver microsomes or recombinant CYP1A2, but not for both isoforms of CYP1A, as done in very recent studies [18,123]. Consequently, the individual contribution of CYP1A1 to the metabolism of established CYP1A2 substrates as summarized in Table 3 remains uncertain, and asks for additional research e fforts. However, even today, these kind of head-to-head comparisons of CYP1A1 and CYP1A2 in drug metabolism are challenging because established manufactures of life science consumables (e.g., Thermo Fisher Scientific and Corning) do not provide microsomal preparations of recombinant CYP1A1, but almost exclusively CYP1A2.

It was estimated by analyzing the metabolic pathways of about 250 frequently used drugs, that CYP1A2 is involved in the biotransformation of about 10% of drugs on the market [10]. CYP1A2-typical biotransformation reactions include N-demethylation of ca ffeine to 1,7-dimethylxanthine (paraxanthine), N-demethylation of clozapine, O-deethylation of phenacetin, and N-demethylation as well as 8-hydroxylation of theophylline. In particular, ca ffeine and phenacetin were frequently used as probe compounds in vitro and for phenotype determination in vivo [11,125]. Due to its high abundance in the human liver, CYP1A2 plays an important role in the metabolism of many clinically important drugs, including antipsychotics (clozapine, olanzapine), antidepressants (duloxetine, agomelatine, mirtazapine), cardiovascular drugs (propranolol, verapamil), non-steroidal anti-inflammatory drugs (NSAID) (phenacetin), the Alzheimer's disease drug tacrine, a cholinesterase inhibitor, the muscle relaxant tizanidine, antiparkinson drugs (rasagilin, ropinirol), and the methylxanthines caffeine, and theophylline [10,11]. Over 100 clinically used drugs have been described to be substrates of CYP1A2 [11]. However, many compounds are subjected to complex metabolism by several CYP enzymes so that the allover contribution of CYP1A2 is limited (~5–20%) and dominated by other pathways. Examples for drugs that are frequently and somewhat misleadingly labelled as typical CYP1A2 substrates are acetaminophen, amitriptyline, bupivacaine, carbamazepine, estradiol, fluvoxamine, haloperidol, imipramine, lidocaine, mianserin, naproxen, ondansetrone, triamterene, warfarin, and zolpidem. Although, CYP1A2 contributes to their metabolism, relevant drug-drug interactions (DDIs) cannot be expected as other metabolic pathways take over in the case of CYP1A2 inhibition. Thus, Table 3 summarizes only drugs whose systemic clearance is assumed to be >25% dependent on CYP1A2 metabolism based on the in vitro phenotyping studies and human pharmacokinetic data, as also suggested by the current Food and Drug Administration (FDA) guidance of drug–drug interactions (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-druginteraction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions). Similar to CYP3A4, CYP1A2 is a rather low affinity but high capacity metabolic enzyme. Thus, only very high concentrations of respective substrates are able to cause competitive inhibition (e.g., by extremely high doses of caffeine).

Endogenous substrates of CYP1A include arachidonic acid, bilirubin, prostaglandins, estrogens, melatonin and retinoic acid [11,126].
