The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency.
BACKGROUND
Carvedilol, a chiral compound possessing nonselective beta- and alpha1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar alpha1-blocking activity; only S-carvedilol possesses beta-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug.


METHODS
The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR < or = 30 ml x min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2 9) dosing.


RESULTS
Mean with (SD) AUC(0-24h) (ng x h x ml(-1)) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng x ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0-24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree.


CONCLUSIONS
Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.
Gehr
T W
TW
Division of Clinical Pharmacology and Hypertension, and Nephrology, Virginia Commonwealth University, Medical College of Virginia, Richmond, USA.
Tenero
D M
DM
Boyle
D A
DA
Qian
Y
Y
Sica
D A
DA
Shusterman
N H
NH
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077261:Carvedilol; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011412:Propanolamines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016037:Single-Blind Method; D013237:Stereoisomerism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol