Identification of fenoldopam prodrugs with prolonged renal vasodilator activity.
Fenoldopam (SK&F 82526) is a short-acting selective dopamine-1 agonist in clinical trials for the treatment of hypertension, congestive heart failure and renal failure. In the present study, we tested various N-ethyl carbamate esters of fenoldopam in the conscious dog instrumented with a femoral arterial Vascular-Access-Port and a renal artery flow probe. Oral administration of SK&F R-82526 at 1 and 3 mumol/kg resulted in transient (30-60 min) dose-dependent increases in plasma fenoldopam levels and renal blood flow. Administration of the 7,8-bis-N-ethyl carbamate ester of R-fenoldopam (SK&F R-106114) and the 4',7,8-tris-N-ethyl carbamate ester of R-fenoldopam (SK&F R-105058) at 1, 3 and 10 mumol/kg p.o. also resulted in dose-dependent increases in plasma fenoldopam levels and renal blood flow; however, both parameters remained elevated for at least 4 hr. Intravenous administration of SK&F R-105058 also resulted in sustained plasma fenoldopam levels and increases in renal blood flow, indicating that slow absorption was not the cause of the sustained effect. The present study indicates that N-ethyl carbamate esters of fenoldopam are fenoldopam prodrugs which result in sustained increases in renal blood flow and plasma fenoldopam levels.
Brooks
D P
DP
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
DePalma
P D
PD
Cyronak
M J
MJ
Bryant
M A
MA
Karpinski
K
K
Mico
B
B
Gaitanopoulos
D E
DE
Chambers
P A
PA
Erhard
K F
KF
Weinstock
J
J
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001552:Benzazepines / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002219:Carbamates / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D015259:Dopamine Agents / Q000378:metabolism*; D005260:Female; D018818:Fenoldopam; D006339:Heart Rate / Q000187:drug effects; D011355:Prodrugs / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism*
D001552:Benzazepines; D002219:Carbamates; D015259:Dopamine Agents; D011355:Prodrugs; D014665:Vasodilator Agents; C068716:SK&F R-105058; C068715:SK&F R-106114; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D018818:Fenoldopam