Pre-clinical pharmacokinetics of the cyclooxygenase-inhibiting nitric oxide donor (CINOD) AZD3582.
The pre-clinical pharmacokinetics of AZD3582 (4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate) and its primary metabolites (naproxen and nitrate) were evaluated. AZD3582 had intermediate and passive intestinal permeability (40 times lower than for naproxen), high systemic plasma clearance (CL), substantial gastrointestinal hydrolysis, intermediate volume of distribution (Vss; >or=3.4 L kg-1) and half-life (t1/2; 7 h), negligible plasma protein binding (approximately 0.1%), low/intermediate oral uptake (>or=13% as intact substance) and low and varying oral bioavailability (mean 1.4% in minipigs and 3.9% in dogs). Following administration of therapeutically relevant oral doses, plasma concentrations of AZD3582 were very low (<or=13 nM in minipigs and <or= 442 nM in dogs; rat data not available) and varying, and accumulation was not apparent. The pharmacokinetics of AZD3582 did not show apparent dose-, time- or gender-related dependency. In blood and intestine, AZD3582 was hydrolysed to naproxen, nitrate and other metabolites. The rate of this conversion was higher in rats than in non-rodents, including man. Despite near-complete to complete uptake of the oral dose, AZD3582 administration resulted in a lower bioavailability (F) of total naproxen than naproxen administration: 55% and 85% relative bioavailability (Frel) in rats and minipigs, respectively. An increased distribution to metabolizing tissues of naproxen (as AZD3582), and thereby enhanced naproxen CL, is believed to be responsible. Following dosing of AZD3582 or naproxen, the t1/2 of naproxen was 5, 9-10 and >40 h in rats, minipigs and dogs, respectively. The Vss and CL for naproxen were small. Plasma protein binding was extensive, and saturation was observed within the therapeutic dose and concentration range. Intake of food prolonged the systemic absorption of naproxen in the minipig. The pharmacokinetics of naproxen did not show apparent time- or gender-related dependency. Following oral dosing of [3H]-, [14C]- and [15N]-AZD3582, most [14C]- and [3H]-activity was excreted in urine and expired air, respectively. Seventeen per cent of [15N] was recovered in minipig urine as [15N]-nitrate. About 30% of [3H]-activity (naproxen and/or naproxen-related metabolites) was excreted in bile and re-absorbed. Concentrations of [14C]-activity (nitrooxy-butyl group and/or its metabolites) in milk were higher than in plasma and [3H]-activity in milk. [3H]- and [14C]-excretion data indicated that intact AZD3582 was not excreted in urine, bile or milk to a significant extent. There was no apparent consistency between tissue distribution of [14C]- and [3H]-activity in the rat, which suggests rapid and extensive metabolism of extravascularly distributed AZD3582. A substantial increase of plasma nitrate levels was found after single and repeated oral doses of AZD3582 in the minipig. No inhibition or induction of CYP450 was found.
Fagerholm
U
U
Clinical Pharmacology, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden. urban.fagerholm@astrazeneca.com
Breuer
O
O
Swedmark
S
S
Hoogstraate
J
J
D000818:Animals; D001646:Bile / Q000737:chemistry; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D008892:Milk / Q000737:chemistry; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics*; D009288:Naproxen / Q000031:analogs & derivatives; D020030:Nitric Oxide Donors / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
D001798:Blood Proteins; D016861:Cyclooxygenase Inhibitors; D009281:Naphthalenes; D020030:Nitric Oxide Donors; C111751:naproxen-n-butyl nitrate; D009288:Naproxen; D003577:Cytochrome P-450 Enzyme System