Richard L. Lalonde

Measurement of underivatized propranolol enantiomers in serum using a cellulose-tris(3,5-dimethylphenylcarbamate) high-performance liquid chromatographic (HPLC) chiral stationary phase.

A commercially available high-performance liquid chromatographic (HPLC) chiral stationary phase (HPLC-CSP) has been used to measure serum levels of d- and l-propranolol. The HPLC-CSP is based upon cellulose–tris(3,5-dimethylcarbamate) and is able to stereochemically resolve d- and l-propranolol without precolumn derivatization using a mobile phase composed of hexane:2-propranol:N,N-dimethyloctylamine (92:8:0.01, v/v/v). Under these conditions the observed stereochemical resolution (α) of the two enantiomers was α = 2.2. A subjects concentration–time curve of the two isomers was determined following the ingestion of 160 mg racemic propranolol.

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 < 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 <0.05), but the volume of distribution was unchanged. Labetalol caused significant ß‐blockade for 8 hours after the last oral dose, but Cimetidine did not alter pharmacologic response. The Emaxmodel 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 < 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant (p < 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.

Mixed‐effects modeling of the pharmacodynamic response to the calcimimetic agent R–568

The parathyroid cell calcium receptor is a novel drug target for affecting parathyroid hormone (PTH) secretion and for treating hyperparathyroidism. R–568 is a calcium receptor agonist that inhibits PTH secretion and increases calcitonin release in preclinical studies. The objective of this study was to evaluate the effect of R‐568 on PTH plasma concentrations in humans.

Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers

In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, Emax,and sigmoid Emaxmodels. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the Emaxmodel was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were Emax33.6±4.5% and EC5018.2±15.6ng/ml for total P and Emax33.5±4.3% and EC501.66±1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50values showed similar intersubject variability. The observed unbound EC50values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50could not be accounted for by variability in P protein binding.

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state

SummaryThe duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days.After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively.The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.

Altered β-Adrenergic Sensitivity and Protein Binding to 1-Propranolol in the Elderly

Summary: The elderly are reported to be less sensitive to the β-blocking effects of propranolol. However, agerelated changes in the stereoselective pharmacokinetics or protein binding of propranolol enantiomers could have confounded the results of previous studies because only 1-propranolol contributes significantly to the β-blocking effects of the racemate. To avoid these confounding variables, we studied 10 young (mean 28 years) and 10 elderly (mean 64 years) subjects, and determined the cardiac P-receptor sensitivity in terms of unbound, active 1-propranolol. The doses of isoproterenol required to increase heart rate (HR) by 25 beats/min were determined before and during a continuous infusion of propranolol. The serum concentration of 1-propranolol was determined by enantioselective high-performance liquid chromatography (HPLC), and the unbound fraction was determined by equilibrium dialysis. The apparent in vivo receptor dissociation constant for unbound 1-propranolol increased from 0.066 ± 0.047 ng/ml in the young to 0.218 ± 0.264 ng/ml in the older group (p<0.05). The unbound fraction was decreased in the older subjects (0.141 ± 0.023 vs. 0.121 ± 0.025, p<0.05) because of an increase in α1-acid glycoprotein concentration (55 ± 11 mg/dl vs. 72 ± 19 mg/dl, p<0.05). Advancing age was associated with a decreased sensitivity to isoproterenol (r s=0.76, p<0.05) and to unbound 1-propranolol (rs=0.45, p<0.05). We conclude that the older subjects have (a) decreased sensitivity to the β-blocking effects of 1-propranolol and to the agonist effects of isoproterenol, and (b) a lower unbound fraction of 1-propranolol

The effect of diltiazem on the disposition of encainide and its active metabolites.

The disposition of encainide is under genetic control. In extensive metabolizers, the drug undergoes extensive first‐pass metabolism to form the active metabolites O‐desmethylencainide (ODE) and 3‐methoxy‐O‐desmethylencainide (MODE). Because diltiazem is a known inhibitor of hepatic oxidative metabolism, the disposition of encainide and its metabolites was studied in eight extensive metabolizers and one poor metabolizer before and after administration of 90 mg diltiazem every 8 hours for 10 days. After diltiazem, the encainide serum AUC values increased in seven of the eight extensive metabolizers, and the percent recovery of encainide in urine increased by 69%. There were no apparent changes in the serum AUC values of the metabolites, suggesting that diltiazem may alter both the formation and the elimination clearances of the metabolites to a similar degree. In the poor metabolizer, encainide serum AUC increased 33% during treatment with diltiazem, but ODE and MODE could not be reliably quantitated. The subjects had no change in QRS, QTc, or JTc intervals after administration of diltiazem. Diltiazem inhibited the first‐pass metabolism of encainide, resulting in increased bioavailability. This appeared to be caused by the inhibition of debrisoquin 4‐hydroxylase and impairment of other unmeasured metabolic pathways for encainide. However, because no change occurs in the systemic exposure to the active metabolites, dosage adjustments in extensive metabolizers are probably not required for patients receiving combination encainide and diltiazem therapy.

Comparison of high pressure liquid chromatography and fluorescence polarization immunoassay methods in a theophylline pharmacokinetic study.

High pressure liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) were compared in a theophylline pharmacokinetic study. Eight healthy subjects received single 600-mg oral doses of two different sustained-release theophylline formulations. Fourteen blood samples were collected over 57 h after each dose, and the serum was analyzed for theophylline using both HPLC and FPIA methods. In comparing the two formulations using HPLC, there was no statistical difference in the area under the curve (AUC), terminal rate constant (k), or time of peak. However, there was a 13% difference in peak theophylline concentration (p less than 0.05). The same statistical conclusions were made for all parameters when using FPIA. When comparing the kinetic parameters determined with each assay, the AUC was 12% greater and the k was 17% smaller with FPIA (p less than 0.05). Orthogonal regression of all serum theophylline concentrations showed that FPIA = 1.04 HPLC + 0.20; r = 0.987, p less than 0.001. Stratification of serum theophylline concentrations into different ranges showed that FPIA overestimated the HPLC results in each range, but the percentage of overestimation was greater at lower concentrations (p less than 0.05). The use of FPIA seems appropriate in comparative studies of theophylline pharmacokinetics; however, the calculated kinetic parameters may differ slightly from those obtained with HPLC.

Dilevalol: An Overview of Its Clinical Pharmacology and Therapeutic Use in Hypertension

Dilevalol is a novel antihypertensive drug that combines nonselective ß blockade with selective ß2‐receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first‐pass hepatic extraction. Its elimination half‐life of approximately 12 hours allows for once‐daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin‐converting enzyme inhibitors and comparable to ß blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high‐density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

The Effects of Encainide versus Diltiazem on the Oxidative Metabolic Pathways of Antipyrine

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p < 0.05) and increased half‐life from 12.7 to 15.9 hours (p < 0.05). Diltiazem reduced the formation rate constants for 3‐hydroxymethylantipyrine by 27% (p < 0.05) and 4‐hydroxyantipyrine by 37% (p < 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 < p < 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half‐life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.