title: Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats.
abstract: Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100- to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats.
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.) christopher.harris@abbvie.com.
authors: Christopher M
authors: CM
authors: Harris
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Scott
authors: S
authors: Mittelstadt
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Patricia
authors: P
authors: Banfor
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Peter
authors: P
authors: Bousquet
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: David B
authors: DB
authors: Duignan
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Gary
authors: G
authors: Gintant
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Michelle
authors: M
authors: Hart
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Youngjae
authors: Y
authors: Kim
authors: Department of Immunology Pharmacology (C.M.H., P.Bo., M.H.) and Department of Drug Metabolism, Pharmacokinetics, and Bioanalysis (D.B.D., Y.K.), AbbVie Bioresearch Center, Worcester, Massachusetts; Department of Safety Pharmacology, AbbVie, North Chicago, Illinois (S.M., P.Ba., G.G., J.S.).
authors: Jason
authors: J
authors: Segreti
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors*; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D010879:Piperazines; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine