Pharmacokinetics and anti-hyperglycaemic efficacy of a novel inhibitor of glycogen phosphorylase, 1,4-dideoxy-1,4-imino-d- arabinitol, in glucagon-challenged rats and dogs and in diabetic ob/ob mice.
OBJECTIVE
To further characterize the properties of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), a recently described novel and potent inhibitor of glycogen phosphorylase and potential anti-diabetic agent, we have determined its pharmacokinetic properties in rats, dogs and mice and compared these to its pharmacodynamic anti-hyperglycaemic efficacy.


METHODS
Male Sprague Dawley rats, beagle dogs and diabetic Umeå ob/ob mice were administered DAB or 14C-DAB at various doses and by different routes and in either the conscious or the unconscious state and with or without glucagon, as appropriate. At different time points thereafter, blood, tissue and urine samples were withdrawn for analyses of DAB or 14C-DAB, and blood samples were taken for glucose concentration.


RESULTS
DAB suppressed the blood glucose excursion in glucagon-challenged rats with an ID100 of 1-2 mg/kg per orally and intravenously and had a pharmacodynamic t50 for 1.6 mg/kg intravenously and for 1.2 mg/kg per orally of 50 and 60 min respectively. The pharmacokinetics of c. 2 mg/kg DAB in rats revealed elimination half-lives of 25 min after intravenous (i.v.) and 49 min after per oral (p.o.) administration; the oral bioavailability was 89%. In rats, DAB was distributed preferentially in liver vs. skeletal muscle and was eliminated predominantly through urine as parent compound. The pharmacokinetics of 4 mg/kg DAB in dogs showed elimination half-lives of 107 min after i.v. and 129 min after p.o. administration with an estimated oral availability of 78%. At 4 mg/kg DAB p.o., glucagon-induced hyperglycaemia in dogs was reduced in a time-dependent manner with an estimated t50 of 4 h. DAB was very rapidly cleared in mice; nevertheless, a dose-dependent reduction of blood glucose of up to 9 mmol/l was seen in diabetic ob/ob mice dosed subcutaneously, with statistically significant effects evident from 30 to 120 min.


CONCLUSIONS
These data show that DAB is nearly completely orally available in rats and dogs and that it can reduce glucagon-induced and spontaneous hyperglycaemia. Inhibition of hepatic glycogen phosphorylase may benefit glycaemic control in patients with type 2 diabetes.
Mackay
P
P
Pharmacology Research I, Novo Nordisk A/S, Novo Allé, Bagsvaerd, Denmark. pm@novonordisk.com
Ynddal
L
L
Andersen
J V
JV
McCormack
J G
JG
D000284:Administration, Oral; D000818:Animals; D001089:Arabinose; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005934:Glucagon; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000097:blood / Q000627:therapeutic use*; D050113:Imino Furanoses; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D017207:Rats, Sprague-Dawley; D013402:Sugar Alcohols / Q000097:blood / Q000627:therapeutic use*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D050113:Imino Furanoses; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D005934:Glucagon; D001089:Arabinose; D024981:Glycogen Phosphorylase