Pharmacokinetic fate of the novel antihypertensive drug naftopidil.
The pharmacokinetics of naftopidil (R,S)-1-[4-(2-methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2 propanol, CAS 57149-07-2) was studied in rats and dogs using 14C-labeled drug in pharmacodynamically effective doses (oral doses: 5/10 mg/kg and intravenous doses: 1/2.5 mg/kg in rats/dogs, respectively). Naftopidil (14C) was rapidly and in high extent absorbed in rats and dogs after oral administration. The absolute bioavailability of the parent compound amounted to 9% in rats and indicates a high first pass effect to in part pharmacodynamically effective metabolites, as was shown in a previous paper. The parent compound and its 14C-metabolites were widely distributed into the periphery, more pronounced in the rat than in the dog, as indicated from comparison of the volumes of distribution and dose corrected Cmax- and AUC0-infinity-values in plasma. Elimination of radioactivity from plasma occurred in rat and dog in a similar rate. Tissue distribution studies in the rat showed highest peak-concentrations in the gastrointestinal (GI) tract (evaluated with contents) due to the predominant biliary elimination, followed by liver, adrenals, pituitary and Harderian glands, lungs, pancreas, kidneys, adipose tissue, bone marrow, aorta, thyroid and lymph nodes. Radioactivity was eliminated from most of the tissues within the first 168 h. Highest fractions of the dose were detected--apart from the GI-tract--in liver, muscle, skin, blood, and kidneys. After repeated administration to rats, accumulation of radioactivity in the 28 tissues examined did not exceed factor 9 or factor 5 in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Peter
G
G
Asta Pharma AG, Department of Biochemistry, Frankfurt/Main, Fed. Rep. of Germany.
Niebch
G
G
Locher
M
M
Borbe
H O
HO
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D009281:Naphthalenes; D010879:Piperazines; C064357:naftopidil