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The transient receptor potential ankyrin 1 (TRPA1) ion channel on peripheral terminals of nociceptive primary afferent nerve fibres contributes to the transduction of noxious stimuli to electrical signals, while on central endings in the spinal dorsal horn, it amplifies transmission to spinal interneurons and projection neurons. The centrally propagating nociceptive signal that is induced and amplified by TRPA1 not only elicits pain sensation but also contributes to peripheral neurogenic inflammation through a peripheral axon reflex or a centrally mediated back propagating dorsal root reflex that releases vasoactive agents from sensory neurons in the periphery. Endogenous TRPA1 agonists that are generated under various pathophysiological conditions both in the periphery and in the spinal cord have TRPA1-mediated pro-nociceptive and pro-inflammatory effects. Among endogenous TRPA1 agonists that have been shown to play a role in the pathogenesis of pain and inflammatory conditions are, for example, methylglyoxal, 4-hydroxynonenal, 12-lipoxygenase-derived hepoxilin A3, 5,6-epoxyeicosatrienoic acid and reactive oxygen species, while mustard oil and cinnamaldehyde are most commonly used exogenous TRPA1 agonists in experimental studies. Among selective TRPA1 antagonists are HC-030031, A-967079, AP-14 and Chembridge-5861528. Recent evidence indicates that TRPA1 plays a role also in transition of acute to chronic pain. Due to its location on a subpopulation of painmediating primary afferent nerve fibres, blocking the TRPA1 channel is expected to have antinociceptive, antiallodynic and anti-inflammatory effects.Sensory information from the periphery is carried to the brain in the form of action potentials. Therefore, the energy induced by sensory stimulation needs to be translated into electrical signals in a process called transduction. In the sense of pain, the transduction of noxious (tissue-damaging or pain-inducing) stimuli takes place at peripheral terminals of nociceptive (pain-mediating) nerve fibres. In light microscopy, the peripheral endings of nociceptive nerve fibres look like free nerve endings. The cell membrane of the free nerve ending expresses various types of receptors that are specialized for transducing mechanical, thermal and/or chemical stimuli into electrical signals. The sensitivity of these membrane receptors varies with the receptor type providing a molecular basis for the submodality selectivity of pain-related signalling.Among the membrane receptors contributing to the transduction of noxious signals on free nerve endings are those belonging to the transient receptor potential (TRP) family of ion channels. The most widely studied member in the TRP family is the transient receptor vanilloid 1 (TRPV1), a channel activated by noxious heat, low pH and capsaicin, the pungent component of chili peppers [1]. Another widely studied member of the TRP family expressed on nociceptive nerve terminals is transient receptor potential ankyrin 1 [2,3], the topic of this MiniReview. TRPA1 is the onl...

Background and ObjectivesDarolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug–drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies.MethodsIn vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3].ResultsIn vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition.ConclusionsDarolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.Electronic supplementary materialThe online version of this article (10.1007/s13318-019-00577-5) contains supplementary material, which is available to authorized users.