Pregnanolone

Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABAA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.

Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis‐free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non‐targeted metabolite profiling by liquid chromatography high‐resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10−5) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3‐O‐glucuronide (GDCA‐3G; p = 1.2 × 10−20 for negative and p = 1.7 × 10−19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3‐O‐glucuronide (GCDCA‐3G; p = 2.7 × 10−16). In both the RF and GBDT models, the GCDCA‐3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA‐3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA‐3G feature. In GBDT, the second and third strongest associations were observed with the GDCA‐3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA‐3G and GDCA‐3G as robust OATP1B1 biomarkers in human plasma.