Pharmacokinetics and blood pressure response of losartan in end-stage renal disease.
BACKGROUND
Losartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD).


OBJECTIVE
To investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines.


METHODS
Patients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration.


RESULTS
The pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable.


CONCLUSIONS
The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.
Sica
D A
DA
Division of Clinical Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0160, USA. DSICA@HSC.VCU.EDU
Halstenson
C E
CE
Gehr
T W
TW
Keane
W F
WF
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D019808:Losartan / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D006435:Renal Dialysis; D012083:Renin / Q000097:blood
D000959:Antihypertensive Agents; D000450:Aldosterone; D012083:Renin; D019808:Losartan