Renal organic anion and cation transporters involved in crisugabalin clearance (OAT/OCT/MATE transporters)

Crisugabalin (HSK16149) is a novel ligand for the α2δ-1 subunit of voltage-gated calcium channels, primarily developed for the treatment of neuropathic pain conditions such as diabetic peripheral neuralgia and postherpetic neuralgia (Source: Zhang et al., 2022, Clinical Pharmacokinetics). The drug is predominantly eliminated through the kidneys, where its clearance is significantly influenced by active tubular secretion in addition to glomerular filtration. This secretory process is mediated by a specific suite of renal transporters, including Organic Anion Transporters 1 and 3 (OAT1, OAT3), Organic Cation Transporter 2 (OCT2), and Multidrug and Toxin Extrusion proteins (MATE1, MATE2-K) (Source: Haisco Pharmaceutical Group, Investigator's Brochure). These transporters, belonging to the Solute Carrier (SLC) families SLC22 and SLC47, facilitate the movement of crisugabalin from the peritubular capillaries into the proximal tubule cells and subsequently into the tubular lumen for excretion. Because these transporters are shared by numerous other medications, they represent a critical site for potential drug-drug interactions (DDIs). Inhibition of these pathways by co-administered drugs, such as probenecid (an OAT inhibitor) or cimetidine (an OCT/MATE inhibitor), can lead to a marked reduction in the renal clearance of crisugabalin, resulting in elevated plasma concentrations and an increased risk of adverse central nervous system effects like somnolence and dizziness. Consequently, the functional status of these transporters is a key determinant of the pharmacokinetic profile and safety of crisugabalin, particularly in patients with renal insufficiency or those undergoing polypharmacy.

Other names

Organic anion transporter 1 (OAT1)Organic anion transporter 3 (OAT3)Organic cation transporter 2 (OCT2)Multidrug and toxin extrusion protein 1 (MATE1)Multidrug and toxin extrusion protein 2-K (MATE2-K)SLC22A6SLC22A8SLC22A2SLC47A1SLC47A2

Active renal tubular secretion of crisugabalin via basolateral uptake (mediated by OAT1, OAT3, and OCT2) and apical efflux (mediated by MATE1 and MATE2-K) in the proximal tubule cells.