Aqueous versus non-aqueous salt delivery strategies to enhance oral bioavailability of a mitogen-activated protein kinase-activated protein kinase (MK-2) inhibitor in rats.
A potent pyridine-containing MK2 inhibitor has recently been internally discovered. In pre-clinical dosing, the low solubility of the neutral form limited oral bioavailability and dose escalation in toxicity studies. A mesylate salt was developed as part of a formulation strategy to enhance both oral bioavailability and dose escalation orally in pre-clinical rat studies. Several non-aqueous systems were used to deliver the mesylate salt, which resulted in varied oral bioavailability. It was found that administration of an aqueous chaser immediately after dosing drastically increased the oral bioavailability of the salt. This finding implies that the quantity of water present in vivo is an important consideration when evaluating salts of free bases with low aqueous solubility in pre-clinical in vivo rat models where limited aqueous vehicle may be presented.
Chiang
Po-Chang
PC
Pfizer Global Research Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA. po-chang.chiang@pfizer.com
South
Sarah A
SA
Daniels
J Scott
JS
Anderson
David R
DR
Wene
Steve P
SP
Albin
Lesley A
LA
Mourey
Robert J
RJ
Selbo
Jon G
JG
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016503:Drug Delivery Systems / Q000379:methods*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008698:Mesylates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014867:Water / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
D047908:Intracellular Signaling Peptides and Proteins; D008698:Mesylates; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012492:Salts; D014867:Water; D000099190:MAP-Kinase-Activated Kinase 2