Bioavailability of labetalol increases with age.

The antihypertensive drug labetalol was administered orally and intravenously to ten hypertensive patients aged between 28 and 75 years. There was a significant increase with age in both bioavailability and half-life of labetalol. Clearance tended to be lower in the elderly subjects. First pass metabolism results in variable oral bioavailability of labetalol which is greater in the elderly and this should be borne in mind when using the drug in this age group.     

Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination

The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor alpha (ERalpha) and pregnane X receptor (PXR) was examined by co-transfecting ERalpha- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.     

Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination

The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor α (ERα) and pregnane X receptor (PXR) was examined by co-transfecting ERα- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.     

Effects of labetalol treatment on the physiological and subjective response to smoked cocaine

Adrenergic receptors mediate some of the physiological and possibly behavioral effects of cocaine. The purpose of this study was to investigate the effect of treatment with a peripherally acting adrenergic blocking drug labetalol on the cardiovascular and subjective response to repeated deliveries of smoked cocaine. In this double-blind, placebo-controlled, crossover study, 12 cocaine users were treated with a single 100 or 200 mg dose of labetalol, or placebo in each of three experimental sessions. Starting 2 h after the medication treatment, subjects received three doses of 0.4 mg/kg smoked cocaine, 30 min apart. Labetalol treatment significantly attenuated the cocaine-induced increases in heart rate and systolic blood pressure. This effect of labetalol on the cardiovascular response did not decrease with repeated cocaine deliveries. The subjective response to smoked cocaine deliveries was not affected by labetalol treatment. These results suggest that labetalol effectively attenuates the systolic blood pressure and heart rate increases induced by repeated doses of smoked cocaine, but does not alter subjective effects.     

The influence of age and smoking on the elimination of disopyramide.

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non-smoking patients compared with young non-smoking subjects (1.54 +/- 0.33 vs 2.12 +/- 0.67 ml kg-1 min-1) (mean +/- s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/- 0.35 vs 1.54 +/- 0.33 ml kg-1 min-1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1-acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/- 0.64 vs 1.16 +/- 0.15 1 kg-1). Steady-state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/- 0.13 micrograms ml-1) than in the elderly (0.90 +/- 0.10 micrograms ml-1). The half-life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non-smokers compared with young subjects.     

Effects of labetalol and propranolol on histamine-induced bronchoconstriction in normal subjects.

1 The effects of oral propranolol (80 mg), labetalol (400 mg) and placebo on blood pressure, pulse rate and FEV1 at rest and after inhaled histamine, have been compared in six healthy male volunteers. 2 At 90 and 120 min after ingestion propranolol reduced the pulse rate and labetalol reduced the blood pressure, thus confirming absorption of each drug. 3 At 120 min propranolol reduced resting FEV1 and enhanced the fall in FEV1 after histamine, whereas the alterations in FEV1 after labetalol did not differ from placebo. 4 These findings suggest that labetalol is less likely than propranolol to cause bronchoconstriction in asthmatic patients.     

The effects of age and chronic liver disease on the elimination of temazepam

Summary The pharmacokinetics of the newer 1, 4 benzodiazepine temazepam were evaluated in 16 healthy subjects aged 18–92 years and in 15 cirrhotic patients, to ascertain the effect of ageing and liver disease. The data were analysed both by classic two compartment and by non-compartmental methods. The mean elimination half-life in the control subjects was 15.5 h, considerably longer than previous estimates. No correlation was found between age and pharmacokinetic parameters. The cirrhotic group showed no statistically significant difference in the pharmacokinetic parameters nor in the urinary recovery of the dose from the control group. Temazepam plasma protein binding was assessed in a second group of 9 cirrhotics of similar severity to the main group and in matched controls. When these binding data were applied to the mean clearance data, a modest although not statistically significant, reduction in free drug clearance was observed in the cirrhotic group. This study adds further support to the observation that drugs which undergo ether glucuronidation have normal elimination patterns in patients with liver disease. Temazepam may prove to be a useful hypnotic sedative in patients with liver disease.     

Effects of labetalol and propranolol on responses to adrenaline infusion in healthy volunteers

The effects of labetalol and propranolol were compared in eight healthy human volunteers using pulse rate and blood pressure changes in response to low rates of adrenaline infusion. Propranolol not only blocked but reversed the positive chronotropic and vasodepressor effects of adrenaline. Labetalol appeared to block these effects only partially. The alpha blocking property of labetalol may have contributed to this difference and hence is unlikely to cause alpha receptor mediated side-effects of endogenously released adrenaline in stress. This model is able to differentiate with great sensitivity between pure beta blockers and alpha beta blocking agents.     

Effects of ampicillin on the elimination of enprofylline in man

The effect of intravenously administered ampicillin on plasma levels and renal clearance of enprofylline was investigated in seven young and six elderly volunteers. On one occasion, each subject received 2 g of ampicillin intravenously, and serum concentrations of ampicillin were followed for 4 hours. On a separate occasion, a loading infusion of enprofylline was administered over 60 min., aiming at a plasma level of 2 micrograms/ml, and followed by a maintenance infusion. During this an infusion of 2 g of ampicillin was given for 10 min., and subsequently, renal clearance and plasma levels of enprofylline were followed for 4 hours. Plasma enprofylline levels increased significantly in the subjects after ampicillin infusion, but the effects on renal clearance of enprofylline were not statistically significant. The magnitude of the effects on enprofylline plasma levels and renal clearance from high doses of ampicillin do not suggest that interaction with beta-lactam antibiotics will be a serious problem for patients on enprofylline treatment.     

Effects of drugs on aminophylline elimination in rats

Effects of phenobarbital, phenytoin, carbamazepine, cimetidine, erythromycin, combination of sulfamethoxazole + trimethoprim (5:1), and rifampicin (rifampin) on the elimination of aminophylline were examined in female rats. Aminophylline was administered i.p. in a dose of 13.33 mg/kg. Blood samples were collected 0.5, 2, 4 and 7 h after the administration of the injection; one measurement was performed from one blood sample. Plasma aminophylline levels were measured by a modified HPLC method. The elimination half-life of the untreated control group (n = 27) was 4.62 h. The pretreatments with drugs examined were carried out by a gastric tube. The half-life of aminophylline after phenobarbital (10 mg/kg, 7 days, n = 29) was 2.09 h; after phenytoin (10 mg/kg, 7 days, n = 29), 2.47 h; after carbamazepine (400 mg/d, 7 days, n = 25), 2.19 h; after cimetidine (in cimetidine-treated group the blood samples were collected 0.5, 4 and 7 h after the aminophylline injection) (40 mg/kg, 7 days, n = 13), 1.77 h; after erythromycin (800 mg/d, 7 days, n = 28), 2.51 h; after the combination of sulfamethoxazole + trimethoprim in ratio of 5:1 (50 mg/kg, 7 days, n = 23), 2.85 h; and after rifampicin (300 mg/kg, 21 days, n = 23), 2.74 h. Sulfamethoxazole presumably interfered with the HPLC examination of aminophylline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of advanced age on the formation and elimination of acetaminophen metabolites by male rats

The effects of aging on acetaminophen metabolism and elimination in male Fischer 344 rats were examined after intravenous injection of 300 mg/kg. Age as a variable had only a small effect on the total clearance of acetaminophen. However, the fraction of administered dose recovered from urine as acetaminophen sulfate and the partial clearance to acetaminophen sulfate decreased while the fraction recovered as acetaminophen glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. Renal clearances of acetaminophen and acetaminophen glucuronide were unchanged while that of acetaminophen sulfate decreased. These data point to an age-related decrease in sulfation and increase in glucuronidation of acetaminophen and further emphasize that the major conjugated metabolites are excreted by renal transport processes that operate under separate control. Moreover, they raise the possibility that advancing age may be accompanied by a general decline in processes that govern sulfate conjugate formation and elimination.     

拉贝洛尔对高血压急症疗效的Meta分析

目的利用Meta分析方法评价拉贝洛尔对高血压急症的疗效与安全性,为临床安全合理用药提供参考。方法以拉贝洛尔、高血压急症为关键词,计算机检索中国数据库,按纳入标准选取拉贝洛尔治疗高血压急症的随机对照试验,用Meta分析方法,运用Rev Man 5.2软件对纳入文献进行分析。结果共纳入5篇文献,Meta结果显示,拉贝洛尔与对照降压药的不良反应也没有明显差异。结论拉贝洛尔对高血压急症患者有明显的降压作用,降压效果和不良反应与对照降压药基本相同。     

Effects of age on the pharmacokinetics of mexiletine

Mexiletine (1-methyl-2-(2, 6-xylyloxy)ethylamine hydrochloride) is an antiarrhythmic drug eliminated primarily by hepatic metabolism. The influence of age on the plasma pharmacokinetics of mexiletine was assessed in seven young and ten elderly healthy subjects. Mexiletine (50 mg) was administered orally three times daily for 10 days. The use of low doses of mexiletine was possible owing to the development of a new fluorescence high performance liquid chromatography method with a limit of sensitivity lower than 20 ng/ml. No differences in the pharmacokinetic parameters of mexiletine related to age were observed. At steady-state plasma concentrations were 0.121 +/- 0.033 microgram-ml in the young volunteers, and 0.135 +/- 0.150 microgram/ml in the older subjects. The elimination t 1/2 was 11.4 +/- 1.78 h in the young subjects and 10.48 +/- 3.06 h in the elderly. The data provide no justification for lowering the recommended dose of mexiletine for older patients.     

Clinical pharmacokinetics of labetalol

Labetalol was the first of a new class of antihypertensive drugs with both alpha- and beta-adrenoceptor blocking properties present in the same molecule. Its efficacy has been confirmed by double-blind studies in the treatment of all grades of hypertension and in angina pectoris. The drug's major dose-related side effect is postural hypotension. The clinical formulation of labetalol consists of equal proportions of 4 optical isomers. One of these (the RR isomer) is probably responsible for the drug's beta-adrenoceptor blockade and another (the SR isomer) produces most of the alpha-blockade. Most of the presently available pharmacokinetic information concerning labetalol is from studies utilising a fluorimetric assay but this has recently been superseded by more specific high-pressure liquid chromatographic (HPLC) procedures. Labetalol is absorbed rapidly after oral administration with peak plasma concentrations generally being achieved within 2 hours. The bioavailability varies from 10% to over 80% in different subjects. Average bioavailability has been reported to correlate with age, with values of approximately 30% in the 30- to 40-year age group and approximately 65% at 80 years. There is also evidence that the bioavailability increases moderately when the drug is taken with food. About 50% of the drug is bound in the plasma. The apparent volume of distribution at equilibrium varies from approximately 200 to over 800L, suggesting that concentration of labetalol occurs in extravascular sites. Radiochemical analysis in animals has shown high levels of accumulation in the lung, liver and kidney with little present in brain tissue. This is in keeping with the relatively low lipid solubility of labetalol. The half-life of labetalol in plasma is 3 to 3.5 hours. The drug is eliminated mainly by hepatic metabolism with the production of several biologically inactive glucuronides which in turn are excreted in the urine and bile. Approximately 85% of labetalol in the blood is removed during a single passage through the liver; thus, like propranolol, labetalol's clearance is probably flow dependent (i.e. it is sensitive to alterations in hepatic blood flow). Small doses of the drug (i.e. 300mg daily) have been shown to reduce antipyrine clearance by approximately 15%, and further studies are necessary to determine whether high doses produce a greater, possibly clinically significant, inhibition of mixed-function oxidase activity. After both single doses and during long term treatment the plasma concentration-time profile of labetalol shows marked variation between different individuals.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of atenolol,labetalol and propranolol on the peripheral circulation in hypertensive patients without obstructive vascular disease

Summary In an observer-blind, randomised cross-over trial, in 12 patients, the effects on the peripheral circulation of antihypertensive doses of atenolol, labetalol and propranolol and placebo were compared. After a placebo period of at least 4 weeks, patients were allocated at random to one of the three active drug treatments. After active treatment for at least 6 weeks and a fall in diastolic pressure (DP) to less than 90 mmHg subjects were switched to the next medication. At the end of each period, photoelectric plethysmography (PHELP) was done on all fingers of one hand cooled over 4 min in water in steps of 3°C from 33° to 12°C, and subsequently warmed in room air (20°C) for a period of 10 min. Blood flow changes during cooling were expressed as a percentage of the initial PHELP value (% PHELP). Areas under the curves, representing the % PHELP/cooling period and % PHELP/warming-up period, showed that within the temperature range normally encountered in daily life, labetalol preserved finger blood flow significantly better than propranolol and marginally better than placebo. With atenolol, finger blood flow was not significantly different from that during the three other regimens, but there were significantly fewer other side-effects. It is concluded that labetalol may be the drug of choice for hypertensive patients treated with beta-blocking agents whose peripheral arterial circulation seems inadequate at low temperatures.     

Effects of labetalol and propranolol on blood pressure at rest and during isometric and dynamic exercise

Summary The influence of intravenous labetalol and propranolol on the blood pressure response to isometric and dynamic exercise was examined in a double blind study in eight, young, normotensive volunteers. Effects were recorded after propranolol 7.5, 15 and 30 mg i. v., and after labetalol 30, 60 and 120 mg i. v. In control experiments saline was administered. Mean blood pressure rose with successive handgrip tests following saline and propranolol, but not after labetalol, and the difference was significant. The total dose of each drug produced the same reduction in heart rate during sub-maximal bicycle exercise. The exercise-induced systolic blood pressure response did not differ between the drugs.     

Intrinsic sympathomimetic activity of labetalol

In intact cats, cumulative doses (0.1-10 mg/kg i.v.) of labetalol produced dose-dependent decreases in heart rate and arterial blood pressure and dose-dependently reduced i.v. phenylephrine induced pressor responses. In spinal cats devoid of resting sympathetic tone, labetalol (1 mg/kg i.v.) produced a sustained elevation of heart rate and a transient fall in arterial blood pressure. In reserpine-pretreated, adrenalectomized cats, labetalol produced quantitatively the same effects as in spinal cats, indicating that the cardiovascular effects observed in cats with no resting sympathetic tone are due to a direct action of labetalol rather than via catecholamine release. The elevated heart rate due to labetalol in spinal cats was reduced by subsequent administration of the beta-adrenergic receptor antagonist, propranolol. Further, pretreatment with propranolol prevented the tachycardic and depressor effects of labetalol in spinal cats. In a separate group of spinal cats, labetalol administered in cumulative doses of up to 1 mg/kg i.v., produced graded increases in heart rate and also dose dependently reduced i.v. isoproterenol-induced tachycardic responses. Pindolol, a beta-adrenergic receptor antagonist with partial beta-agonist activity, produced similar effects in spinal cats at cumulative doses of 1-30 micrograms/kg. These results indicate that the alpha- and beta-adrenergic receptor antagonist, labetalol possesses partial beta-adrenergic receptor agonist activity. This intrinsic sympathomimetic action of labetalol appears to be more sustained on cardiac than on vascular beta-adrenergic receptors.