THE PHARMACOKINETICS AND METABOLISM OF ALPHA-TRINOSITOL(D-MYO-INOSITOL 1,2,6-TRISPHOSPHATE) - STUDIES INVOLVING INTRAVENOUS-INFUSION IN RATS, METABOLISM IN HUMAN PLATELETS AND LEUKOCYTES, AND DEPHOSPHORYLATIONBY BOVINE ALKALINE-PHOSPHATASES

In the present study the disposition of alpha-trinositol in rats, with special emphasis on its metabolism was investigated. The drug was adm inistered as an intravenous bolus dose (18.2 mu mol/kg) immediately fo llowed by a short term intravenous infusion (48.8 mu mol/kg/h) of [H-3 ]alpha-trinositol over 1.5 h. In the plasma samples, only unchanged al pha-trinositol, InsP(2), InsP(1), inositol and water were detected whi ch indicates that during metabolism of alpha-trinositol in the rat onl y these metabolites are formed. The plasma concentration-time profile of alpha-trinositol showed a very fast decline following the cessation of the intravenous infusion, which probably is due to rapid metabolis m and therefore a relative high total clearance of the drug, 23 +/- 4. 3 ml/min/kg. The volume of distribution at steady state is 3.5 +/- 1.5 l/kg in the rat. To gain further insight into the metabolism of alpha -trinositol, we have also examined the possible metabolism by blood ce lls using intact human platelets, platelet homogenates, intact human n eutrophils and also alpha-trinositol incorporated into human platelets using reversible electropermeabilization. Intact platelets and neutro phils showed little ability to metabolize alpha-trinositol when measur ed over a one hour incubation period. Platelet homogenates also showed little ability to metabolize alpha-trinositol under conditions where inositol 1,4,5 trisphosphate was rapidly metabolized to both inositol bisphosphate and inositol tetrakisphosphate. When alpha-trinositol was encapsulated into human platelets during reversible electropermeabili zation significant metabolism was observed, with the main metabolite b eing InsP(1). We have also examined alpha-trinositol metabolism with a lkaline phosphatases from bovine intestinal mucosa, kidney and liver. The intestinal enzyme showed extensive dephosphorylation of alpha-trin ositol to Ins(1,2)P-2 and Ins(2)P-1 The kidney and liver enzyme showed slower dephosphorylation of alpha-trinositol with the end product bei ng Ins(1,2)P-2. (C) 1997 Elsevier Science B.V.