Pharmacodynamic and pharmacokinetic characterisation of RBx 7796: a novel 5-lipoxygenase inhibitor.
OBJECTIVE
RBx 7796, a 5-lipoxygenase inhibitor, was evaluated in in vivo efficacy models, in vitro ADME and in vivo pharmacokinetic models.


METHODS
RBx 7796 was evaluated for inhibition of 5-lipoxygenase enzyme and release of LTB4 from isolated rat and human neutrophils. RBx 7796 was tested in allergic bronchoconstriction model in Balb/c mice and LPS induced airway hyperreactivity model in rats. RBx 7796 was evaluated for metabolic stability in liver microsomes and cytochrome P450 inhibition potential. Pharmacokinetic profile of RBx 7796 was also determined in rat and dog.


RESULTS
RBx 7796 inhibited 5-lipoxygenase enzyme and inhibited release of LTB4 from neutrophils. RBx 7796 also inhibited early and late airway reactivity following allergen challenge in mouse model. LPS induced increase in airway reactivity was blocked by RBx 7796. Compound was found to be stable in liver microsomes and devoid of major cytochrome P450 inhibition potential. The oral bioavailability of RBx 7796 in rat and dog was 83 % and 47 %, respectively. Following repeated daily administration, compound did not exhibit any sign of accumulation and/or tendency to induce its own metabolism.


CONCLUSIONS
The results suggest that RBx 7796 is an inhibitor of 5-lipoxygenase enzyme that is orally efficacious in two different models of airway reactivity. The molecule also demonstrated acceptable pharmacokinetic profile warranting further development.
Shirumalla
R K
RK
Department of Pharmacology, Ranbaxy Research Laboratories, Gurgaon, Haryana, 122015, India.
Sharma
P
P
Dastidar
S G
SG
Paliwal
J K
JK
Kakar
S
S
Varshney
B
B
Singh Saini
G
G
Sattigeri
V
V
Salman
M
M
Ray
A
A
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000276:immunology; D000001:Calcimycin / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007476:Ionophores / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012492:Salts / Q000737:chemistry
D007476:Ionophores; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; C530469:RBx 7796; D012492:Salts; D007975:Leukotriene B4; D000001:Calcimycin; D001094:Arachidonate 5-Lipoxygenase; D006918:Hydroxyurea