Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a major public health problem, since 300,000,000 people in the world display a glomerular filtration rate (GFR) below 60 mL/min/1.73m². Patients with CKD have high rates of complications and comorbidities. Thus, they require the prescription of numerous medications, making the management of patients very complex. The prescription of numerous drugs associated with an altered renal- and non-renal clearance makes dose adjustment challenging in these patients, with frequent drug-related adverse events. However, the mechanisms involved in this abnormal drug clearance during CKD are not still well identified. We propose here that the transcription factor, aryl hydrocarbon receptor, which is the cellular receptor for indolic uremic toxins, could worsen the metabolism and the excretion of drugs in CKD patients.

Keywords: AhR; drug clearance; uremic toxins.

Figure 1

The effect of uremic toxins derived from tryptophan on drug metabolism via aryl hydrocarbon receptor(AhR). Indoxyl sulfate (IS), kynurenine (K), kynurenic acid (KA), and indole-3-acetic acid (IAA), produced from dietary tryptophan, are ligands of the transcription factor AhR. AhR, upon activation by these uremic toxins, can modulate the expression of genes involved in the metabolism and in the efflux of drugs. In addition, these toxins can inhibit directly these enzymes and these transporters.