Pharmacokinetics and metabolism of a selective PDE5 inhibitor (UK-343,664) in rat and dog.
1. UK-343,664 is a novel potent and selective PDE5 inhibitor. Plasma clearances in the male and female rat were high (120 and 54 ml min(-1) kg(-1)), giving rise to short elimination half-lives (0.2 and 0.3h respectively). Lower clearance in dog (14 ml min(-1) kg(-1)) was the primary factor resulting in a longer elimination half-life (3.7 h). The higher clearance in rat than dog was in agreement with in vitro metabolism rates in hepatic microsomes. 2. The volume of distribution was lower in rat (1.3-2.11 kg(-1)) compared with dog (4.61 kg(-1)) probably due to increased plasma protein binding in rat (96 versus 81% in dog). 3. Oral bioavailabilities were 2, 12 and 70% in the male and female rat and dog respectively. Tmax < or = 0.5 h in all animals. 4. In multiple oral dose studies, increased systemic exposure was seen with increasing dose up to doses of 200 mg kg(-1) in rat and 150 mg kg(-1) in dog. A marked super-proportional increase in the male rat indicated a capacity-limited clearance at high doses. 5. At the maximal dose of 200 mg kg(-1) in the female rat, no clinical signs were observed after 14 days of treatment. Only minimal signs were recorded in the male rat and dog at the highest dose levels investigated. 6. After single oral or intravenous doses of [14C]-UK-343,664, the majority of radioactivity was excreted in the faeces of both species. 7. UK-343,664 was extensively metabolized in both rat and dog. The major primary pathways in dog involved piperazine N-deethylation and loss of a two carbon fragment from the piperazine ring (N,N'-de-ethylation). More extensive metabolism in the rat included additional notable metalbolites arising from hydroxylation and lactamization of the piperazine ring, which were only minor metabolites in the dog.
Walker
D K
DK
Department of Drug Metabolism, Pfizer Global Research and Development, Sandwich, UK. don_walker@sandwich.pfizer.com
Beaumont
K C
KC
Comby
P
P
Evans
K M
KM
Gedge
J I
JI
Halliday
R C
RC
Roffey
S J
SJ
Wright
P A
PA
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011744:Pyrimidinones / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013045:Species Specificity
D001798:Blood Proteins; D002250:Carbon Radioisotopes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; C450961:UK 343,664; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat