Nifedipine pharmacokinetics during preterm labor tocolysis.

Nifedipine, a calcium entry blocker, has known relaxing effects on the myometrium. Thirteen women in preterm labor received nifedipine for tocolysis. Blood samples obtained serially during treatment and at the time of delivery were assayed for maternal and neonatal nifedipine concentrations. The peak concentration of nifedipine during sublingual therapy ranged from 23.4 to 197.9 ng/ml and reflected substantial interpatient variability. The mean (+/- SD) measurable trough value in patients who received 20 mg of nifedipine orally every 6 hours was 7.2 +/- 5.5 ng/ml. The maternal mean half-life of nifedipine was 81 minutes (range 49 to 137 minutes). At delivery, neonatal nifedipine levels were nondetectable in 6 of the 11 neonates available for study; in 5, values ranged from 29.5 to 1.8 ng/ml. From these results we conclude that both sublingual and oral nifedipine treatment results in variable but usually measurable maternal plasma concentrations and that placental transfer of nifedipine occurs.

Comparison of age-related changes in prostaglandin E1 and beta-adrenergic responsiveness of vascular smooth muscle in adult males.

Aging in humans is associated with a general decline in beta-adrenergic receptor responsiveness. Whether this is a consequence of a defect at the receptor level or along the adenylate cyclase pathway is not known. Using a technique to measure compliance of dorsal hand veins, we investigated the venodilatory response to isoproterenol and prostaglandin E1 (PGE1), which interact with distinct membrane-bound receptors but activate the same adenylate cyclase system. Studies were conducted in 7 young (Y, less than 30 years) and 7 elderly (E, greater than 60 years) healthy male volunteers. Dilatation induced by isoproterenol (mean +/- SD) was 43 +/- 8% in E vs 97 +/- 17% in Y, p = .003. However, PGE, produced complete relaxation in both Y and E subjects (122 +/- 17% vs 97 +/- 19% respectively, p = .270). The sensitivity to PGE1 was not significantly different between the Y and E. Our results demonstrate that PGE1 is a potent venodilator in humans and that the age-related decline in vascular response is specific to beta-adrenoceptor agonists and does not reflect a generalized loss in responsiveness to adenylate cyclase coupled receptors.

Plasma antipyrine half-life can be determined from urine data.

Antipyrine half-life has been determined from measurements of antipyrine concentrations in spontaneously voided urine specimens in eleven subjects, studied on a total of forty-seven different occasions while receiving no drugs, interferon or ketoconazole. Plasma and saliva half-lives show good intrasubject correlation. Plasma and urine half-lives show good intrasubject correlation provided total urine output is at least 1.1 l day-1. The range of intrasubject correlation coefficients for plasma and urinary half-lives was 0.76 to 0.98, with a median value of 0.85. Saliva and urine half-lives show good intrasubject correlation, with the range of intrasubject correlation coefficients from 0.74 to 0.98, and with a median value of 0.75. There is a small but consistent bias towards shorter urinary half-life estimates; this averaged 0.75 h for the plasma-urine studies and 0.192 h for the saliva-urine studies. There were parallel changes in antipyrine half-life estimated from plasma and urine for one of our subjects who received multiple doses of recombinant beta-interferon and had a 150% increase in antipyrine half-life over the study period.

Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man.

Beta adrenergic relaxation of vascular smooth muscle, mediated by cyclic AMP, is blunted with age in a variety of experimental animals. The applicability of these observations to man is uncertain. The dorsal hand vein technique provides an excellent method to examine the direct effects of aging on vascular responsiveness. Thirty-nine healthy male volunteers over the age range of 19 to 79 were studied. No differences in vascular responsiveness to phenylephrine, an alpha adrenergic agonist, were found for either the ED50 (dose producing 50% vasoconstriction) or Emax (maximum vasoconstriction attained). In marked contrast, vascular relaxation induced by isoproterenol, a beta adrenergic agonist, was significantly different in both the ED50 (dose producing 50% of maximum relaxation from a preconstricted state) and Emax (maximum relaxation attained). ED50 +/- S.E.M. for the youngest and oldest deciles were 8.9 +/- 2.3 and 60 +/- 17.0 ng/min, respectively (P less than .05); Emax +/- S.E.M. were 96.7 +/- 3.3 and 37.7 +/- 8.7%, respectively (P less than .001). Nitroglycerin, a smooth muscle relaxant whose effects are not mediated through the cyclic AMP system, was also used to examine the specificity of this blunted response to isoproterenol. Almost complete relaxation was achieved with the infusion of nitroglycerin in the older group. These results suggest that aging is associated with a specific decrease in beta adrenoreceptor-mediated vascular relaxation.

In vivo interaction of the enantiomers of disopyramide in human subjects.

Disopyramide, an antiarrhythmic agent, is marketed as a racemic mixture of two enantiomers. The racemic drug has unusual pharmacokinetic properties because of its concentration-dependent binding to plasma proteins in the therapeutic plasma concentration range. This study examined, in healthy subjects, the individual pharmacokinetic properties of both total and unbound d- and 1-disopyramide in plasma after intravenous administration of each enantiomer separately (1.5 mg/kg). Also investigated is the pharmacokinetics of total d- and 1-disopyramide in plasma after intravenous administration of a pseudoracemate. Both d- and 1-disopyramide are found to exhibit concentration-dependent binding to plasma proteins, with d-disopyramide being more avidly bound at lower concentrations. The stereoselective, concentration-dependent binding to plasma proteins resulted in distinct pharmacokinetic properties when the enantiomers were given together as the pseudoracemate. d-Disopyramide had a lower plasma clearance and renal clearance, a longer half-life, and a smaller apparent volume of distribution than 1-disopyramide. However, when the enantiomers were administered separately, there were no differences in the clearance, renal clearance, and volume of distribution between enantiomers calculated from either total or unbound drug concentrations. The results reveal an important pharmacokinetic interaction between the enantiomers of disopyramide when given as a racemic mixture, which may be dose-dependent and is not apparent upon administration of the enantiomers separately.