Transporter Proteins as Therapeutic Drug Targets-With a Focus on SGLT2 Inhibitors.

Membrane transporters interact not only with endogenous substrates but are also engaged in the transport of xenobiotics, including drugs. While the coordinated function of uptake (solute carrier family-SLC and SLCO) and efflux (ATP-binding cassette family-ABC, multidrug and toxic compound extrusion family-MATE) transporter system allows vectorial drug transport, efflux carriers alone achieve barrier functions. The modulation of transport functions was proved to be effective in the treatment strategies of various pathological states. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are the drugs most widely applied in clinical practice, especially in the treatment of diabetes mellitus and heart failure. Sodium taurocholate co-transporting polypeptide (NTCP) serves as virus particles (HBV/HDV) carrier, and inhibition of its function is applied in the treatment of hepatitis B and hepatitis D by myrcludex B. Inherited cholestatic diseases, such as Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) can be treated by odevixibat and maralixibat, which inhibit activity of apical sodium-dependent bile salt transporter (ASBT). Probenecid can be considered to increase uric acid excretion in the urine mainly via the inhibition of urate transporter 1 (URAT1), and due to pharmacokinetic interactions involving organic anion transporters 1 and 3 (OAT1 and OAT3), it modifies renal excretion of penicillins or ciprofloxacin as well as nephrotoxicity of cidofovir. This review discusses clinically approved drugs that affect membrane/drug transporter function.

Management of adults with Alagille syndrome.

Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.

Ileal Bile Acid Transporter Blockers for Cholestatic Liver Disease in Pediatric Patients with Alagille Syndrome: A Systematic Review and Meta-Analysis.

Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic review and meta-analysis presents the latest evidence for ileal bile acid transport (IBAT) blockers in AGLS patients in order to improve their efficacy. This study adhered to PRISMA 2020 Statement guidelines. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane library was conducted from inception until 23 October 2022. A combination of the following keywords was used: Alagille syndrome, therapeutics, treatment, therapy. Meta-analytical outcomes included effect directions of end-line changes in serum bile acids (sBAs), Itch Scale scores (ItchRO), Multidimensional Fatigue Scale scores, pediatric quality of life (QL), alanine aminotransferase (ALT), and total bilirubin. A total of 94 patients across four trials were enrolled and received maralixibat, odevixibat, or a placebo. There was a significant reduction in ItchRO scores by 1.8 points, as well as in sBAs by 75.8 µmol/L. Both the Multidimensional Fatigue Scale and Pediatric QL scale were also improved by 11.4 and 8.3 points, respectively. However, ALT levels were raised by 40 U/L. The efficacy of IBAT inhibitors across current trials was noted. Future trials may focus on the optimization of dosing regimens, considering gastrointestinal side effects and drug-induced ALT elevation in AGLS patients.

Serum Bile Acid Profiling and Mixed Model Analysis Reveal Biomarkers Associated with Pruritus Reduction in Maralixibat-Treated Patients with BSEP Deficiency.

Progressive familial intrahepatic cholestasis (PFIC) is a debilitating disease manifest by severe cholestasis, intractable pruritus and growth delay that ultimately leads to liver failure or transplantation. Maralixibat (MRX) was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome. The aim of this study was to determine whether specific changes in the composition of the serum bile acid metabolome could predict pruritus response to treatment. Serum BAs (sBA) and 7α-hydroxy-4-cholesten-3-one (7α-C4), a surrogate marker of BA synthesis, were monitored by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry over 72 weeks in PFIC patients with mild to moderate non-truncating bile salt export pump (BSEP) mutations (n = 19) treated with MRX. The weekly itch reported outcome observer (ItchRO[Obs]) score measured pruritus severity. Linear mixed models (LMM) were applied to explore the effects of individual sBA profiles and their relationship to pruritus response. Changes in the composition of sBA correlated with pruritus improvement. Notably, the trajectory of serum total and individual BA species and 7α-C4 were significantly associated with ItchRO[Obs] score (p < 0.05). These results reveal that beyond simple total sBA concentrations, specific changes to the BA metabolome are associated with pruritus reduction in patients with BSEP deficiency, thus providing further insight into causal relationship of bile acids and pruritus.

Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders.

Biliary atresia is a rare cholestatic liver disease that presents in infants and rapidly advances to death in the absence of intervention. As a result of blockage or destruction of the biliary tract, bile acids accumulate and drive inflammation, fibrosis, and disease progression. The standard of care, Kasai portoenterostomy (KPE), is typically performed shortly after diagnosis (currently at ~ 2 months of age) and aims to restore bile flow and relieve cholestasis. Nevertheless, most patients continue to experience liver injury from accumulation of bile acids after KPE, since there are no known effective therapeutics that may enhance survival after KPE. Improving cholestasis via interruption of the enterohepatic circulation of bile acids may directly attenuate hepatic bile acid retention and reduce the risk of early organ failure. Directly addressing intrahepatic accretion of bile acids to avoid inherent bile acid toxicities provides an attractive and plausible therapeutic target for biliary atresia. This review explores the novel therapeutic concept of inhibiting the sole ileal bile acid transporter (IBAT), also known as ASBT (apical sodium-bile acid transporter, encoded by SLC10A2), as a means to reduce hepatic bile acid concentration after KPE. By reducing return of bile acids to the cholestatic liver, IBAT inhibitors may potentially lessen or delay liver damage associated with the hepatotoxicity and cholangiopathy of bile acid accumulation. The clinical programs of 2 IBAT inhibitors in development for the treatment of pediatric cholestatic liver diseases, maralixibat and odevixibat, are highlighted.