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Journal of Clinical Pharmacology May 1990Penbutolol and carteolol are two new long acting, nonselective beta-adrenergic blockers which have been approved for the treatment of systemic hypertension. Both drugs... (Comparative Study)
Comparative Study Review
Penbutolol and carteolol are two new long acting, nonselective beta-adrenergic blockers which have been approved for the treatment of systemic hypertension. Both drugs have intrinsic sympathomimetic activity (partial agonist activity), however, less than that seen with pindolol. They appear to cause less resting bradycardia than propranolol, have no effect on lipids and lipoproteins, and have favorable side effect profiles.
Topics: Arrhythmias, Cardiac; Carteolol; Chemical Phenomena; Chemistry; Coronary Disease; Humans; Hypertension; Penbutolol; Propanolamines
PubMed: 2189902
DOI: 10.1002/j.1552-4604.1990.tb03479.x -
DICP : the Annals of Pharmacotherapy Apr 1990Penbutolol is a new beta-adrenergic blocking drug approved for the treatment of hypertension. It is a noncardioselective beta-blocker and has intrinsic sympathomimetic... (Review)
Review
Penbutolol is a new beta-adrenergic blocking drug approved for the treatment of hypertension. It is a noncardioselective beta-blocker and has intrinsic sympathomimetic activity. The drug is approximately four times as potent as propranolol when taken orally. After oral administration, it is almost completely absorbed and peak plasma concentrations are achieved within 1.0 to 2.25 hours. Penbutolol is extensively metabolized in the liver by hydroxylation and glucuronidation. Active metabolites have not been identified. Only four to six percent of the parent drug is eliminated in the urine unchanged and dosage adjustment in renal insufficiency does not appear to be necessary. The mean terminal half-life of penbutolol is 17.6 to 26.5 hours. The duration of the hypotensive effect is approximately 24 hours. Current dosing guidelines recommend initiating therapy with 20 mg/d administered once a day. Optimum hypotensive effect occurs at dosages of 20-40 mg/d with little additional benefit observed above this range. Penbutolol appears to be well tolerated. The adverse effect profile is similar to other beta-blockers.
Topics: Animals; Humans; Penbutolol; Propanolamines
PubMed: 2183495
DOI: 10.1177/106002809002400412 -
European Journal of Clinical... 1988The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by...
The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4'-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4'-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta 2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.
Topics: Adrenergic beta-Antagonists; Adult; Double-Blind Method; Heart Rate; Humans; Male; Middle Aged; Penbutolol; Physical Exertion; Propanolamines; Radioligand Assay; Random Allocation
PubMed: 2906875
DOI: 10.1007/BF00637597 -
European Journal of Clinical... 1985Beta-adrenoceptor binding of (-) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human...
Beta-adrenoceptor binding of (-) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (approximately 99%) the apparent Ki-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the Ki was approximately 40-70 ng/ml. That value is comparable to the IC50-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with beta-adrenoceptors was not affected to the same extent by inclusion of plasma protein binding approximately 80%, apparent Ki-value approximately 7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at beta-adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using beta-adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of beta-adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Blood Proteins; Buffers; Heart Rate; Humans; Male; Penbutolol; Propanolamines; Protein Binding; Receptors, Adrenergic, beta; Time Factors
PubMed: 3000796
DOI: 10.1007/BF00544083 -
European Journal of Clinical... 1985The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment....
The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment. A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13-14% of the administered dose, which is consistent with extensive metabolism of the drug. After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased. It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.
Topics: Adult; Female; Glucuronates; Humans; Hypertension; Kidney Diseases; Kinetics; Male; Middle Aged; Penbutolol; Propanolamines
PubMed: 4076321
DOI: 10.1007/BF00547425 -
Mutation Research Oct 1990The genotoxic potential of the beta-adrenergic blocker penbutolol was assessed using the Ames and HGPRT tests, unscheduled DNA synthesis (UDS) and alkaline elution...
The genotoxic potential of the beta-adrenergic blocker penbutolol was assessed using the Ames and HGPRT tests, unscheduled DNA synthesis (UDS) and alkaline elution assays. In the Ames test, penbutolol was tested for cytotoxicity and genotoxic activity in concentration ranges of 0.8-500 micrograms/plate and 0.1-125 micrograms/ml in the HGPRT, UDS and alkaline elution assays. In the Ames test penbutolol showed significant toxicity above 500 micrograms/plate. In the mammalian cells (V79) used for the HGPRT test and A459 cells used for alkaline elution and UDS assays, penbutolol was cytotoxic at concentrations above 30 micrograms/ml. In another series of experiments, male Wistar rats were treated i.p. with penbutolol (1, 10 and 100 mg/kg) and after 2 h liver nuclei were isolated and formation of single DNA-strand breaks was measured. The results of the present study demonstrate the absence of genotoxic activity of penbutolol in the 5 strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537 and TA1538) and in the strain of Escherichia coli WP2 uvrA in the presence or absence of metabolic activation. In V79 cells, penbutolol showed no mutagenic effects at the HGPRT locus in the presence or absence of metabolic activation. Additionally, no significant incorporation of [3H]thymidine into the DNA in the UDS test or formation of DNA-strand breaks in the alkaline elution assay was detected in the non-toxic concentration range of penbutolol with or without metabolic activation. Furthermore, penbutolol did not cause DNA damage in liver nuclei isolated from penbutolol-treated rats.
Topics: Animals; Biotransformation; Cell Line; Cell Survival; Cricetinae; DNA Damage; DNA Replication; Male; Mutagenicity Tests; Mutation; Penbutolol; Rats; Rats, Inbred Strains; Salmonella typhimurium; Time Factors
PubMed: 2233830
DOI: 10.1016/0165-1218(90)90039-5 -
Klinische Wochenschrift Jul 1986The pharmacokinetics and dynamics of the D- and L-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The pharmacokinetics and dynamics of the D- and L-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose of L-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ between L-penbutolol and placebo. In Study Two, subjects received 40 mg D-penbutolol, L-penbutolol, and placebo on three occasions. Total clearance of D-penbutolol was higher than for the L-isomer (43.7 vs 15.9 ml/min/kg; P less than 0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 micrograms/ml X h; P less than 0.005). In contrast, direct conjugates of L-penbutolol achieved higher serum concentrations than conjugates of D-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf for D-penbutolol, L-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.
Topics: Administration, Oral; Adult; Biotransformation; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kinetics; Male; Metabolic Clearance Rate; Penbutolol; Propanolamines; Stereoisomerism
PubMed: 3762014
DOI: 10.1007/BF01726915