Akio Ebihara

Effect of diltiazem on the pharmacokinetics of propranolol, metoprolol and atenolol

SummaryThe pharmacokinetic interaction between diltiazem and three β-adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg.The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo.The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.

The effects of age and gender on the stereoselective pharmacokinetics of verapamil

The effects of age and gender on the pharmacokinetics of verapamil stereoisomers were examined. Eighty milligrams of racemic verapamil was given orally to 12 young and 12 elderly healthy subjects, half of whom were women. The area under the plasma concentration—time curves (AUC) of (S)‐ and (R)‐verapamil were greater in the elderly group than in the young group [(S)‐/(R)‐verapamil (mean ± SD), 214.4 ± 123.0/1582.2 ± 763.0 and 50.4 ± 36.5/584.9 ± 252.4 ng · hr/ml for the elderly and young groups, respectively (p< 0.001/p < 0.001)]. Conversely, the apparent oral clearance values of (S)‐and (R)‐verapamil were significantly smaller in the elderly group than in the young group [(S)‐/(R)‐verapamil (mean ± SD), 4.8 ± 3.0/0.53 ± 0.21 and 22.5 ± 21.3/1.30 ± 0.67 L/hr/kg for the elderly and young groups, respectively (p < 0.01/p< 0.001)]. The ratio of apparent oral clearance of (S)‐ to (R)‐verapamil was significantly smaller in the elderly group than in the young group. As a consequence, the negative chronotropic and dromotropic effect of verapamil was observed in the elderly group. This study suggests that the effect of age on metabolism was greater for (S)‐verapamil than for (R)‐verapamil.

Dose Dependent Effect of Diltiazem on the Pharmacokinetics of Nifedipine

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double‐blind, Latin square method. On the fourth day, a 20‐mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half‐life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P < .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol × hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P < .05, 30 mg vs 90 mg, 0.1 < P < .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose‐dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose‐dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.

Daily variations in platelet aggregation and adhesion in healthy subjects.

Platelet aggregation is known to show a morning rise. The present study was undertaken to examine whether platelet aggregation and adhesion show a peak in the afternoon. Platelet aggregation stimulated by 4 microM of adenosine diphosphate, 1 micrograms/ml of collagen, 4 microM of epinephrine and 0.5 mM of arachidonic acid, and platelet adhesion determined by platelet retention on a glass bead column were measured for a period of 28-hour with an interval of 4 hours in 6 healthy subjects. Platelet aggregation in response to 4 different aggregating agents showed a bimodal daily variation with peaks in the morning and in the afternoon. However platelet adhesion only showed a peak in the morning. Previous studies have demonstrated the increases in the onset of acute myocardial infarction (MI) in the morning and afternoon periods. As enhanced platelet aggregation is involved in the development of acute MI, the present study suggests that the rise in platelet aggregation contributes to the increase in acute MI in the morning and in the afternoon. The present study suggests that the enhancement of platelet adhesion, which might be involved in thromboembolic events, may be another triggering factor for the onset of acute MI.

Chronopharmacological study of furosemide in rats

The present experiment was undertaken to determine whether or not the effects of furosemide depend upon the administration time and, if so, to study the mechanism(s) for these variations. After administration of furosemide (5 mg/kg) in Wistar rats at 10:00 or at 22:00, urine volume and urinary excretion of sodium, furosemide, and prostaglandin E2 (PGE2) were measured. Urine volume and urinary excretion of sodium and furosemide, but not PGE2, were significantly greater when furosemide was administered at 10:00 than when it was administered at 22:00. There was a good correlation between the urinary output of furosemide and the urine volume, or the urinary sodium. It is concluded that the effects of furosemide vary with the administration time and these variations depend upon the amount of furosemide secreted in urine.

Differences of Chronopharmacokinetic Profiles Between Propranolol and Atenolol in Hypertensive Subjects

Previous studies have shown that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the night dosage than after the morning dosage in nocturnal rodents. The present study examines whether such a difference in chronopharmacokinetic proxies between lipophilic and hydrophilic agents also exists in humans. Propranolol (20 mg), a lipophilic β‐blocker, or atenolol (50 mg), a hydrophilic β‐blocker, was given orally to 13 hypertensive patients at 9:00 am (day trial) or 9:00 pm (night trial) by a crossover design. Plasma concentrations of propranolol and its metabolites, 4‐hydroxypropranolol and naphthoxylactic acid, and atenolol were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after treatment. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) of propranolol in the day trial were significantly greater than those in the night trial Time to maximum plasma concentration (tmax) was significantly shorter in the day trial. No significant difference was observed in the elimination half‐life between the two trials. There were similar administration time‐dependent changes in the Cmaxfor 4‐hydroxypropranolol and naphthoxylactic acid. On the other hand, although the Cmax of atenolol was greater and its tmax was shorter in the day trial, the differences did not reach significance. These results suggest that propranolol, but not atenolol is absorbed more rapidly after the morning dosage than after the night dosage. Based on these findings, the authors speculate that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the morning dosage than after the night dosage in humans.

Influences of Bathing and Hot Weather on the Pharmacokinetics of a New Transdermal Clonidine, M‐5041T

The influences of bathing and hot weather on plasma concentrations of clonidine were examined during application of a new transdermal clonidine system, M‐5041T, in eight healthy volunteers. An M‐5041T patch containing 6 mg of clonidine was applied on the right chest for 96 hours during winter with or without bathing (40°C for 5 minutes) and also during summer without bathing. Plasma concentrations and urinary excretion of clonidine were determined for a 160‐hour period after application. Plasma concentrations of clonidine in the winter trials did not differ significantly with or without bathing. Plasma drug concentration as a whole was significantly higher in the summer trial than in the winter trial, however. The maximum plasma concentration (Cmax), area under the plasma concentration‐time curve (AUC), and urinary excretion (Ae) of clonidine also tended to be higher in the summer trial. These results suggest that plasma levels of clonidine are higher after application of M‐5041T during hot weather. Although the period of bathing used in this study was short, the influence of bathing seems to be negligible.

Chronopharmacological study of furosemide in rats: (II) influence of β-adrenoceptor blockade

We have previously demonstrated a time-dependent variability in the diuretic effect of furosemide in rats. The present study was undertaken to evaluate the influence of beta-adrenoceptor blockade on these time-dependent variations. Furosemide (5 mg/kg) was administered intra-arterially in Wistar rats at 1000 hrs (03HALO) or at 2200 hrs (15HALO) with pretreatment with either propranolol (10 mg/kg) or atenolol (10 mg/kg). Urine was collected for 60 min after furosemide administration and urinary excretion of sodium and furosemide were determined respectively. Propranolol pretreatment abolished the temporal variations observed in urine volume, urinary sodium and furosemide levels during the observation periods. With atenolol pretreatment, however, all these variables were significantly greater at 1000 hrs (03HALO) than at 2200 hrs (15HALO) as observed in the previous study. These results suggest that the beta-adrenoceptor-mediated stimuli, which is blocked by propranolol but not by atenolol, is responsible for the time-dependent changes in the diuretic effect of furosemide.

Clinical Pharmacology of Multiple‐Dose Losartan, an Angiotensin II Receptor Antagonist, in Patients with Essential Hypertension

The pharmacokinetic and pharmacodynamic alterations of multiple doses of losartan, an angiotensin II receptor antagonist, were examined in nine patients with essential hypertension. Participants were given placebo once daily for the first 7 days (from day −7 to day −1), and then 50 mg of losartan for the next 9 days (from day 1 to day 9). The 24‐hour blood pressure was measured on days −1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E‐3174, were obtained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, and at the end of the study. Pharmacokinetic parameters after the seventh dose, including maximum plasma concentration (Cmax and time to Cmax (tmax) of losartan and E‐3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of losartan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma clearance (ClUA) increased significantly during repeated administration with losartan. These values returned to pretreatment levels after the end of treatment. These results suggest that although the pharmacokinetic profiles of losartan and E‐3174 do not change during repeated administration, the blood pressure lowering effect in hypertensive patients is greater after multiple doses than after a single dose.

Effect of α1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation

Objectives: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of α-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different α1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these α1-adrenoceptor antagonists in human subjects.Method:In thirteen healthy male subjects (20–42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg).Results:Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The α1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil.Conclusion:These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative α1-adrenoceptor blocking potency of drugs.