Pharmacokinetics and Bioavailability of Carvedilol in Patients with Liver Cirrhosis

Neugebauer, G; Gábor, M; Reiff, K.

doi:10.2165/00003495-198800366-00026

Cited by 27 publications

(26 citation statements)

References 2 publications

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“…In another study Neugebauer et al [14] demonstrated an AUC of 292 ng. h. ml-1 after oral administration of 50 mg carvedilol to 10 young (mean age 29.5 y) male subj ects, confirming their previous results [6,7,11]. In accordance with these results, the effects of oral administration of 50 mg carvedilol on blood pressure and heart rate in patients with chronic renal failure seem to be comparable to those in essential hypertensive patients [2][3][4].…”

supporting

confidence: 88%

“…h. ml-~ [10]; terminal halflife tI/z 14.6 (4.0) h [8], 7.0 (1.9) or7.6 (3.9) h [9]; Morgan et al [10] reported a half-life of 5.0 (1.2) or 5.3 (0.7) h, but it is not clear from their paper whether that half-life represents the terminal half-life. The age distribution in the above studies was 61 (6) y [8], 45 (10) y [9], and < 50 y (patient Group 1) or 65-80 y (patient Group 2) [11]. In contrast to the above results, one study reported an AUC of 348 ng-ml, h ~ (170-611) and a terminal half-life of 6.4 h Table 3.…”

Section: Discussionmentioning

confidence: 72%

“…However the mean age was 26 (6) y and the healthy controls were of over-average size (height 180 (10) cm; weight 77 (9) kg; body surface 1.96 (0.15) m 2) [6,7,11]. Therefore those findings cannot confidently be compared with the above studies [8][9][10], or with the present investigation.…”

mentioning

confidence: 54%

“…Extensive pharmacokinetic studies of carvedilol have been done in healthy volunteers, in hypertensive patients and in patients with liver cirrhosis, but its pharmacokinetics in hypertensive patients with chronic renal failure has only been reported in a preliminary paper [6][7][8][9][10][11][12]. In addition, little information is available in the literature about the pharmacokinetics of the metabolites of carvedilol in hypertensive patients with chronic renal failure [12].…”

Section: Discussionmentioning

confidence: 99%

“…102 (8) 91 (11) 86 (15) 84 (16) 81 (16) 89 (14) 91 ( 82 (9) 80 (10) 75 (7) 75 (5) 79 (8) 78 (6) 76 (9) (4.1-14.6) in 20 healthy male volunteers [6,7,11]. However the mean age was 26 (6) y and the healthy controls were of over-average size (height 180 (10) cm; weight 77 (9) kg; body surface 1.96 (0.15) m 2) [6,7,11].…”

mentioning

confidence: 99%

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Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure

Krämer

Ress

Erley

et al. 1992

Eur J Clin Pharmacol

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Summary.The pharmacokinetic and acute systemic haemodynamic effects of a single oral dose of 50 mg carvedilol has been studied in 24 hypertensive patients with chronic renal failure. The patients were stratified into 3 groups according to the creatinine clearance: 1 51-90 ml-min-~; II 26-50 ml. min-1; III 425 ml-rain-1.The area under plasma level time curve AUC, the elimination half-life tl/2, the maximum plasma concentration Cm~, the time to peak concentration tm~x were not significantly different between groups, whereas the amount of unchanged drug or metabolite excreted in urine A~ and the renal clearance CLR of carvedilol and its metabolites M2, M4, M5 were significantly decreased in Group III. Blood pressure and heart rate decreased in all 3 groups of patients after acute administration of 50 mg carvedilol. Mild adverse effects were reported in 6 patients. Despite a decrease in the renal clearance of carvedilol and of its metabolites with decreasing kidney function, its main pharmacokinetic parameters remained unchanged. The present results suggest that the dose of carvedilol need not be reduced in hypertensive patients with chronic renal failure.Key words: Hypertension, Carveditol; chronic renal failure, pharmacokinetics, adverse effects Carvedilol is a non-selective /3-adrenoceptor blocking drug with vasodilating activity primarily due to c¢~-adrenoceptor blocking properties, and to a minor extent to calcium channel blocking activity (little or no contribution to the antihypertensive effect) at a high concentration [1]. The total clearance of carvedilol is 590 ml-min-1, its renal clearance is 4 ml. rain-1, and the distribution volume is 132 1 [6,7]. The absolute bioavailability of carvedilol has been estimated to be 24 %, indicating some degree of first pass extraction, and the protein binding is 95 % [6,7].Carvedilol has been shown to be effective in the treatment of patients with essential and renal hypertension, and angina pectoris [2][3][4][5]. Extensive pharmacokinetic studies of carvedilol have been done in healthy volunteers, in hypertensive patients and in patients with liver cirrhosis, but its pharmacokinetics in hypertensive patients with chronic renal failure has only been reported in a preliminary paper [6][7][8][9][10][11][12]. In addition, little information is available in the literature about the pharmacokinetics of the metabolites of carvedilol in hypertensive patients with chronic renal failure [12]. Pharmacological activity is attributed only to carvedilol metabolites M2, M4 and M5 (Sponer, unpublished). The chemical structures of carvedilol and its metabolites are displayed in Fig. 1.The pharmacokinetics and effects of acute oral administration of 50 mg carvedilol in hypertensive patients with chronic renal failure of differing severity have now been investigated. Patients and methods

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supporting

confidence: 88%

Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure

Krämer

Ress

Erley

et al. 1992

Eur J Clin Pharmacol

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Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics

et al. 1993

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As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective beta-adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac-carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)-carvedilol exceeded those of (S)-carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism.

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Assay and Disposition of Carvedilol Enantiomers in Humans and Monkeys: Evidence of Stereoselective Presystemic Metabolism

Fujimaki

Murakoshi

Hakusui

1990

Journal of Pharmaceutical Sciences

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Pharmacokinetics and Bioavailability of Carvedilol in Patients with Liver Cirrhosis

Cited by 27 publications

References 2 publications

Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure

Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure

Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics

Assay and Disposition of Carvedilol Enantiomers in Humans and Monkeys: Evidence of Stereoselective Presystemic Metabolism

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