Labetalol Concentrations Research Articles

Lipid Emulsions Inhibit Labetalol-Induced Vasodilation in the Isolated Rat Aorta.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.

Does Labetalol Trigger False Positive Drug Testing Results?

Labetalol, an α- and β-adrenergic antagonist used to treat hypertension in pregnancy has been blamed for causing false-positive amphetamine and methamphetamine results. In this study, we tested 3 concentrations of labetalol prepared with 4 specimen types (urine, plasma, meconium, and umbilical cord tissue), for amphetamine, methamphetamine, and several other drugs with screen and confirmation tests. Residual drug-free specimens were pooled. Labetalol hydrochloride dissolved in methanol was used to prepare spikes in triplicate per specimen type (2.7, 50, and 100 μM), which were tested with 41 previously validated drug tests performed by immunoassay or liquid chromatography tandem mass spectrometry (LC-MS/MS). Labetalol triggered false-positive amphetamine and methamphetamine results by immunoassay in meconium but did not trigger positive results for any of the targeted drugs or drug metabolites tested by LC-MS/MS. No positive results were generated by any immunoassay or LC-MS/MS test included in the study, when challenged with high concentrations of labetalol in urine, plasma, or umbilical cord tissue. In summary, false-positive results can be generated by labetalol when tested by immunoassay, but false-positive results are not expected when testing is performed by highly specific analytical approaches such as LC-MS/MS.

Supramolecular interaction of labetalol with cucurbit[7]uril for its sensitive fluorescence detection.

This work studied the host-guest interaction between cucurbit[7]uril (CB[7]) and labetalol in acidic aqueous solution and proposed a simple competitive method for fluorescence detection of labetalol. The binding constant of labetalol-CB[7] was (1.83 ± 0.22) × 10(6) M(-1), which was greater than those of palmatine-CB[7], berberine-CB[7], and coptisine-CB[7] complexes. The fluorescence intensity of palmatine-CB[7], berberine-CB[7], and coptisine-CB[7] complexes decreased linearly with increasing concentration of labetalol ranging from 0.014 to 2.06, 0.014 to 1.15, and 0.034 to 1.23 μM, respectively. Based on the competitive interaction, the proposed detection method for labetalol showed limits of detection of 4.9 nM, 4.9 nM, and 12.0 nM, respectively, and was successfully applied for the determination of labetalol in human urine samples with good precision and recoveries from 95.4% to 102.5%. Moreover, it could be employed to monitor the time-dependent concentration of labetalol in urine from a healthy volunteer after oral medication. The superstructure-based competitive mode provided a promising fluorescence assay strategy for various potential applications.

In Vitro Assessment of Clevidipine Using the Profilin1 Hypertensive Mouse Model

Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model.

Comparison of the Permeability of Metoprolol and Labetalol in Rat, Mouse, and Caco-2 Cells: Use as a Reference Standard for BCS Classification

The purpose of this study was to investigate labetalol as a potential high permeability reference standard for the application of Biopharmaceutics Classification Systems (BCS). Permeabilities of labetalol and metoprolol were investigated in animal intestinal perfusion models and Caco-2 cell monolayers. After isolating specific intestinal segments, in situ single-pass intestinal perfusions (SPIP) were performed in rats and mice. The effective permeabilities (Peff) of labetalol and metoprolol, an FDA standard for the low/high Peff class boundary, were investigated in two different segments of rat intestine (proximal jejunum and distal ileum) and in the proximal jejunum of mouse. No significant difference was found between Peff of metoprolol and labetalol in the jejunum and ileum of rat (0.33 ± 0.11 × 10(-4) vs 0.38 ± 0.06 × 10(-4) and 0.57 ± 0.17 × 10(-4) vs 0.64 ± 0.30 × 10(-4) cm/s, respectively) and in the jejunum of mouse (0.55 ± 0.05 × 10(-4) vs 0.59 ± 0.13 × 10(-4) cm/s). However, Peff of metoprolol and labetalol were 1.7 and 1.6 times higher in the jejunum of mouse, compared to the jejunum of rat, respectively. Metoprolol and labetalol showed segmental-dependent permeability through the rat intestine, with increased Peff in the distal ileum in comparison to the proximal jejunum. Most significantly, Peff of labetalol was found to be concentration-dependent. Decreasing concentrations of labetalol in the perfusate resulted in decreased Peff compared to Peff of metoprolol. The intestinal epithelial permeability of labetalol was lower than that of metoprolol in Caco-2 cells at both apical pH 6.5 and 7.5 (5.96 ± 1.96 × 10(-6) vs 9.44 ± 3.44 × 10(-6) and 15.9 ± 2.2 × 10(-6) vs 23.2 ± 7.1 × 10(-6) cm/s, respectively). Labetalol exhibited higher permeability in basolateral to apical (BL-AP) compared to AP-BL direction in Caco-2 cells at 0.1 times the highest dose strength (HDS) (46.7 ± 6.5 × 10(-6) vs 14.2 ± 1.5 × 10(-6) cm/s). The P-gp inhibitor, verapamil, significantly increased AP-BL and decreased BL-AP direction transport of labetalol. Overall, labetalol showed high Peff in rat and mouse intestinal perfusion models similar to metoprolol at a concentration based on HDS. However, the concentration-dependent permeability of labetalol in mice due to P-gp and the inhibition study with verapamil in Caco-2 cells indicated that labetalol is not an ideal reference standard for BCS classification.

CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects

The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol. The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms. Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞. Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

Resonance light-scattering method for the determination of labetalol using uranyl acetate and aniline blue

A sensitive and convenient method for determining labetalol has been developed based on resonance light-scattering using ternary complex of aniline blue (AB), uranyl ion (UO 2 2+) and labetalol. At pH 6.0–7.0, labetalol reacted with AB and UO 2 2+ to form an ion-association complex that resulted in considerable resonance light-scattering (RLS) characterized with a peak at 356 nm. The RLS was successfully applied to the determination of labetalol. The intensity of RLS ( I RLS) at 356 nm linearly depended on the concentration of labetalol ranging from 4.0 × 10 − 7 to 2.4 × 10 − 4 mol L − 1 . The lower detection limit was 2.1 × 10 − 7 mol L − 1 . The present method is highly selective to labetalol and can successfully be applied to the determination of labetalol in human urine.

Analytical applications of electrode sensitive to labetalol in pharmaceuticals

AbstractThe analytical properties of an ion-selective electrode sensitive to labetalol with a liquid membrane, based on ion-pair complexes with sodium tetraphenylborate (TPB-Na+) are described. The studied electrode can be used for the determination of labetalol hydrochloride as a protonated form of labetalol in pharmaceuticals. The calibration curve, e.g. EMF=f(pCLabHCl) is linear in the range from 10−5 to 10−2 mol L−1 with a correlation coefficient of 0.9992 and slope of 61.13 mV/decade, which is close to the Nernstian slope. The detection limit of the examined electrode is 7.20×10−6 mol L−1. The influence of pH of the tested solutions on the formulation of the electrode is not as considerable since the electrode works correctly in the pH range 3.0–8.0. The main attributes of the developed electrode are: stability, good reproducibility of EMF and short response time, close to 30 seconds depending on labetalol concentration in the solution. The electrode shows good selectivity for many inorganic ions. The selectivity for drug cations is weaker due to the structural similarity of the interfering cations to labetalol. The results of labetalol determination using direct potentiometry in drugs such as Pressocard (Polpharma) and Trandate (GlaxoWellcome) were compatible with the quantity of labetalol declared by the manufacturer, and with parallel UV spectrophotometric and HPLC determinations.

Neonatal Adrenergic Blockade Following Single dose Maternal Labetalol Administration

A single 30 mg intravenous dose of labetalol given 20 minutes prior to cesarean delivery at 35 weeks of gestation for severe pregnancy-induced hypertension was associated with symptoms of beta-adrenergic blockade (hypoglycemia, bradycardia, hypotension) in preterm twins. The infants were subsequently found to have therapeutic labetalol concentrations (180 and 150 ng/mL) in umbilical cord blood. The pharmacology of transplacental labetalol is reviewed and potential mechanisms for neonatal beta-adrenergic blockade are discussed.

Labetalol in hypertension during the third trimester of pregnancy: its antihypertensive effect and pharmacokinetic-dynamic analysis.

The hypotensive effect, kinetics, and concentration-response relationship of labetalol, alpha beta- and alpha 1-adrenoceptor blocking drug, were studied in seven women with a moderate-to-severe hypertension (averaged diastolic blood pressure [DBP] of 100 to 120 mm Hg measured during a 1- to 2-day hospitalization period) during the third trimester of pregnancy who received the oral twice-daily doses of 150 to 450 mg. These dosages were individually selected by attaining a therapeutic goal of DBP < or = 100 mm Hg or systolic blood pressure (SBP)/DBP reduction of > 30/15 mm Hg, as compared with the pretreatment value, at any time during the 12-hour dosing interval for a 3- to 5-day dosage escalation period. Labetalol concentrations in plasma were measured by a high-performance liquid chromatography with fluorescence detection, and the plasma drug concentration-response relationship was analyzed by a sigmoidal Emax model. Labetalol decreased significantly (P < 0.05 to 0.01) the pretreatment SBP/DBP (166.3 +/- 5.2/110.3 +/- 3.0 mm Hg, mean +/- SEM) without any recognizable side-effects during the twice-daily dosing period in the mothers. Peaked concentrations occurred at 1 hour postdose in all patients. The elimination half-lives ranged from 4.3 to 6.9 hours, and the apparent oral clearance from 31.9 to 73.3 mL/min/kg. The pharmacodynamic parameters (Emax and EC50) analyzed by the Emax model revealed a 3- to 5-fold interindividual variability. The gestational ages at delivery ranged from 34 to 37 weeks, and the birth weights were < 2000 g in 6 of the 7 neonates. Four neonates developed respiratory distress syndrome after delivery, and one infant died of pulmonary hypoplasia 3 months later. The results indicate that 1) labetalol orally administered in a twice-daily regimen as done in this study is an effective antihypertensive drug in women with hypertension during late pregnancy, and 2) interindividual variability in the kinetic factor (e.g., oral clearance) as well as that in the pharmacodynamic factor (e.g., EC50) appear to be related to the overall variability in the hypotensive responsiveness to the drug. However, whether labetalol and/or hypertension per se would have been related to the fetal outcome remains unanswered from the present study.

Sensitive high-performance liquid chromatographic method for direct separation of labetalol stereoisomers in biological fluids using an α 1-acid glycoprotein stationary phase

A chiral high-performance liquid chromatographic assay for the separation of the four stereoisomers of labetalol, an antihypertensive, in biological fluids has been developed. Baseline separation of the isomers was achieved using an α 1-acid glycoprotein stationary phase. No interference from endogenous substances was observed following extraction from various biological fluids obtained from pregnant (ewe and fetus) and non-pregnant sheep. The concentration of the individual isomers of labetalol was determined by first measuring the total concentration of racemic labetalol obtained from an achiral assay followed by reassay of each sample by the chiral method after which, by using the estimate of the percentage of each individual isomer, the individual concentration of each of the four isomers was determined. The mobile phase was 0.02 M phosphate buffer containing 0.015 M tetrabutylammonium phosphate. The pH of the mobile phase was adjusted to 7.10. The detector was set at an excitation wavelength of 230 nm and emission wavelength of 400 nm to monitor the nascent fluorescence intensity of the isomers of labetalol. The limit of detection of the individual isomers was 0.15 ng (0.6 ng of injected racemic labetalol). The assay was linear over the range 0.6–15.0 ng of labetalol (injected) with the intra- and inter-day mean coefficients of variation being less than 9.0 and 6.0%, respectively. Application of the assay in the study of pharmacokinetics of the stereoisomers of labetalol in sheep following administration of racemic labetalol has been demonstrated.

Performance characteristics of a Labetalol‐H plus‐tetraphenylborate selective electrode

AbstractThe construction and performance characteristics of an ion selective membrane electrode for labetalol drugs in protonated form, based on their ion‐pair complexes with sodium tetraphenylborate (TPB‐Na+) incorporated in a poly(vinyl chloride) matrix, are described. The Labetalol‐H+ selective electrode can be used practically for the determination of the pharmaceutical compound by direct potentiometry. The potentiometric sensor exhibits near‐Nernstian response from 10−2 M to about 10−5 M, with a slope of 55 mV/decade of concentration and detection limit of 4.46 × 10−6 M. The influence of changing the membrane characteristics, pH, and temperature of the test solution on the electrode potential are studied. The response time varies from a few seconds to several minutes, depending on labetalol concentration. The selectivity of the electrode for Lab‐H+ toward primary, secondary, tertiary, and quaternary amines is investigated. Determination of Lab‐H+ in pharmaceutical tablets is performed using the proposed membrane electrode. No interference from any excipients in the tablets was observed.

The effects of labetalol and dilevalol on isolated cardiovascular preparations of the guinea-pig and rat.

Differing effects of labetalol and dilevalol on cardiovascular preparations have been reported. I have studied the effects of labetalol and dilevalol on the contractile responses of the rat and guinea-pig left atria and rat portal vein. On the guinea-pig left atria low concentrations of labetalol (> or = 10(-8) M) and of dilevalol (> or = 10(-7) M) inhibited to a small extent the responses to electrical cardiac stimulation, which is indicative of membrane stabilizing activity. Labetalol (> or = 3 x 10(-8) M) and dilevalol (> or = 10(-8) M) caused surmountable antagonism of the isoprenaline responses of the atria and the pA2 values were 8.60 and 8.98 at the beta 1-adrenoceptors of the rat left atria and 7.90 and 8.31, respectively, on the guinea-pig left atria which has functional beta 1- and beta 2-adrenoceptors. Labetalol and dilevalol (both at > or = 10(-7) M) attenuated the spontaneous contractile activity of the rat portal vein and the attenuation to labetalol at 10(-6) M was abolished by ICI 118,551 which illustrates that the labetalol-induced attenuation is beta 2-adrenoceptor mediated. The isoprenaline attenuation responses of the portal vein were inhibited by labetalol and dilevalol (both at > or = 10(-7) M) and the pA2 value for the labetalol at beta 2-adrenoceptors was 7.59. It is concluded that labetalol and dilevalol are beta 1-adrenoceptor selective antagonists.

The effect of beta blocking drugs on lipid peroxidation in rat heart in vitro.

Beta-adrenergic receptor blocking drugs include a structurally related class of drugs that are employed clinically to treat a variety of cardiovascular disorders. Since these drugs exert additional nonspecific effects including membrane stabilization, representative samples including atenolol, dilevolol, labetalol, metoprolol and propranolol were studied to determine their influence on lipid peroxidation. Homogenates or liposomes of adult rat hearts were incubated in the presence of various concentrations of propranolol or equivalent concentrations of dilevolol, labetalol, metoprolol or atenolol. Lipid peroxidation was stimulated with 50 microM FeSO4, 5 microM t-butyl hydroperoxide (homogenates) or 0.2 mM citrate FeSO4 (liposomes) plus O2. Lipid peroxidation, as assessed by both the thiobarbituric acid reaction and chemiluminescence, was reduced in a dose-dependent manner as the propranolol concentration was increased from 1 to 10 mM. The five beta-adrenergic receptor blocking drugs reduced lipid peroxidation both in crude homogenates and in liposomes; their effectiveness was related to their lipophilicity. Dilevolol, propranolol, labetalol and metoprolol at a concentration of 20 mM reduced lipid peroxidation by 45%, 37%, 35% and 28%, respectively. The hydrophilic blocker atenolol was ineffective in reducing lipid peroxidation even at elevated concentrations. Lipophilic beta-blocking drugs apparently are capable of exerting an antioxidant effect in protecting membrane lipids against peroxidation.

Labetalol pharmacokinetics and pharmacodynamics: Evidence of stereoselective disposition

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with cimetidine administration (58.7 +/- 23.3 to 32.9 +/- 13.2 ml/min/kg; p less than 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 +/- 5.3 to 17.7 +/- 3.7 ml/min/kg; p less than 0.05), but the volume of distribution was unchanged. Labetalol caused significant beta-blockade for 8 hours after the last oral dose, but cimetidine did not alter pharmacologic response. The Emax model provided a good description of the concentration-effect relationship. At peak labetalol concentrations after oral administration, (R,R)-labetalol concentrations were significantly lower than those of the other three stereoisomers (p less than 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p less than 0.05) for only the (S,R)-, (S,S)-, and (R,S)-isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)-labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)-labetalol.

Effect of labetalol on human platelet function.

1. The effects of the alpha-beta-adrenergic antagonist labetalol on the activation of human platelets by adrenaline and other aggregating stimuli have been investigated. 2. Labetalol inhibited platelet aggregation and secretion induced by collagen and the second phase of aggregation caused by ADP, platelet activating factor, adrenaline and ionophore A23187. Adrenaline-induced platelet activation was inhibited by the lowest labetalol concentration. The response to Na arachidonate was minimally affected and the arachidonate-induced thromboxane B2 generation was only partially prevented. 3. The pre-incubation with low concentration of ionophore A23187 overcame labetalol's inhibition of collagen-induced platelet aggregation. 4. Labetalol did not influence intraplatelet cyclic AMP levels. 5. The present investigation provided evidences that the modulation of human platelet function by labetalol could be related also to a decreased Ca2+ availability.

Interindividual and intraindividual variability in labetalol pharmacokinetics.

The between-subject and within-subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7-day washout separated each administration phase. Plasma concentration-time data for labetalol were obtained over the 24-hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean V beta/F, Vdss/F, TBC/F, t1/2 beta, and AUC tau 0 for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 micrograms.hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect "significant" differences in the disposition of labetalol.

Electrophysiological effects of labetalol on canine atrial, cardiac Purkinje fibres and ventricular muscle.

1. Using conventional microelectrode techniques for the intracellular recordings of the membrane potential, the effects of labetalol were studied on cardiac Purkinje, atrial and ventricular muscle fibres of the dog. 2. Labetalol (1-10 microM) reduced, in a concentration-dependent manner, the action potential amplitude (APA) and the maximum rate of rise of the action potential (Vmax) in Purkinje fibres. 3. The action potential duration (APD) was decreased in Purkinje fibres but significantly increased in ventricular fibres after small concentrations of labetalol (1-3 microM). The atrial fibres were not very sensitive to labetalol. 4. Depolarization of the cardiac Purkinje fibres by increasing the external potassium concentration (8-12 mM), potentiated the labetalol effects on APA and Vmax but blocked its effects on the APD. 5. The effects of labetalol on Vmax of Purkinje fibres were dependent on the frequency of stimulation. 6. The ratio of the effective refractory period to the APD was increased both in normally polarized and depolarized Purkinje fibres after treatment with labetalol (10 microM). 7. Labetalol (10 microM) shifted the membrane responsiveness curve of Purkinje fibres by about 10 mV in the hyperpolarizing direction. 8. The slow response obtained in K-depolarized, Ba-treated Purkinje fibres was not significantly affected by labetalol (10-100 microM). 9. It is suggested that labetalol can exert Class I and Class III antiarrhythmic actions in cardiac muscle of the dog in vitro.

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension

Pharmacodynamics and pharmacokinetics of labetalol, a combined α- and β-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 ± 8 vs 25 ± 13 mm Hg, p < 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 ± 10 mm Hg) and young (17 ± 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 ± 16 vs 16 ± 14 mm Hg, p < 0.001) and similar decreases in standing diastolic BP (21 ± 7 vs 17 ± 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 ± 16 vs 17 ± 7 mm Hg systolic and 24 ± 6 vs 12 ± 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol Pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 ± 1.05 vs 0.326 ± 0.490 ng/ml · mm Hg −1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 ± 0.063 vs 0.406 ± 0.303 ng/ml · beats/min −1 (p < 0.05), with 2 elderly patients showing no decrease in heart rate. Labetalol intravenous elimination half-life was markedly prolonged in the elderly (8.5 ± 4.1 vs 2.9 ±1.3 hours, p < 0.001) because of a decrease in total clearance (13.9 ± 6.4 vs 19.4 ± 6.2 ml/min/kg, p < 0.05). After oral labetalol administration, peak concentration was greater in elderly patients (214 ± 123 vs 109 ± 60 ng/ml, p < 0.05). Labetalol absolute bioavailability was not signficantly different between elderly and young patients (19.6 ± 9.6 vs 14.5 ±10.3%). The combination of increased antihypertensive effect and decreased clearance suggest that smaller labetalol doses may be required in elderly hypertensive persons to achieve antihypertensive effects comparable to those in young hypertensive persons.

Combined use of an automated sample processor and a polymer-based high-performance liquid chromatographic column to determine the pharmacokinetics of labetallo in man

An improved high-performance liquid chromatographic (HPLC) assay has been developed for the analysis of labetalol in human plasma. The method is based on the combined use of an automated sample processor, reversed-phase analysis on a microparticulated polymer-based HPLC column and fluorescence detection. The pH stability of the polymeric column packing material allowed the use of a mobile phase adjusted to pH 9.5, which was optimal for the fluorescence of labetalol. Assay validation was undertaken over the labetalol concentration range 2–100 ng/ml. Calibration curves were essentially linear, and the mean coefficient of variation was 5.3%. The assay has been used for the analysis of clinical samples in support of pharmacokinetic studies.