1 The transepithelial transport of the P-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2.2 The basal-to-apical transport (secretion) of ['4C]-celiprolol (50 jLM) was 5 times higher than apical-tobasal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-toapical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3 Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 ± 0.23 mm and Vm,, of 113 ± 11 pmol/106 cells min-'. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4 The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5 The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N'-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems.6 The secretion of celiprolol was also inhibited by other P-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours. Three subjects were studied in a three-way crossover of fenoldopam at doses of 0.025, 0.10, and 0.50 microgram/kg/min. Fenoldopam decreased diastolic blood pressure and increased pulse rate without changing systolic blood pressure. Fenoldopam produced dose-related increases in para-aminohippuric acid clearance up to 75% at the 0.50 microgram/kg/min dose. This increase in renal blood flow was accompanied by increases in urine volume, water, and solute excretion; glomerular filtration rate was unchanged. Doses greater than 0.25 microgram/kg/min caused flushing and nasal congestion. The dopamine receptor antagonist metoclopramide (0.1 mg/kg/hr) did not block the systemic hemodynamic effects of fenoldopam but attenuated the increase in para-aminohippuric acid clearance. Fenoldopam plasma levels achieved steady state between 30 and 120 minutes after the start of the infusion and were linear with respect to infusion rate. Our findings show that intravenous fenoldopam causes systemic arteriolar vasodilation, accompanied by renal vasodilation and increased sodium excretion.

The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6-mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline.

Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide. Under conditions of abuse, which involve the administration of high repetitive doses, methamphetamine can produce considerable neurotoxic effects. However, recent evidence from our laboratory indicates that low doses of methamphetamine can produce robust neuroprotection when administered within 12h after severe traumatic brain injury (TBI) in rodents. Thus, it appears that methamphetamine under certain circumstances and correct dosing can produce a neuroprotective effect. This review addresses the neuroprotective potential of methamphetamine and focuses on the potential beneficial application for TBI.

The potential for enhanced systemic absorption of intranasal triamcinolone acetonide was explored in patients with inflamed nasal mucosa. Twelve allergic rhinitis patients with documented nasal inflammation, and 12 healthy volunteers, each received a single, therapeutic, 400-micrograms dose of triamcinolone acetonide in each nostril. Blood was obtained at fixed time points after the dose, and plasma concentrations of triamcinolone acetonide were determined by radioimmunoassay. There were no statistically significant differences in any of the derived pharmacokinetic parameters (maximum plasma triamcinolone acetonide concentrations [Cmax], time to maximum plasma triamcinolone concentrations [Tmax], elimination half-life [t1/2], and area under the plasma concentration-time curve [AUC0-12] from 0 to 12 hours) between treatment groups. A once-a-day, chronic regimen (6 weeks) of triamcinolone acetonide was also administered to five patients with allergic rhinitis. Pharmacokinetic parameters were similar to the parameters derived from healthy volunteers after acute administration. There was no evidence of drug accumulation. The results of this study indicate that acute and chronic intranasal administration. The results of this study indicate that acute and chronic intranasal administration of therapeutic doses of triamcinolone acetonide to patients with inflamed nasal mucosa does not result in enhanced systemic drug absorption or accumulation.

No abstract

No abstract

Cimetidine pharmacokinetics and metabolism were studied in 2 full-term and 1 premature neonates. All infants demonstrated the capacity to eliminate cimetidine via both metabolic and renal routes. The half-life of cimetidine ranged from 3.4 to 2.1 h, and decreased as total body clearance increased. These alterations in pharmacokinetics were felt to represent developmental and maturational differences, primarily in renal function. In contrast to the 60% routinely seen in adults, approximately 90% of the administered dose was recovered in the urine of the full-term infants as cimetidine and its known metabolites. Cimetidine sulfoxide and hydroxymethyl cimetidine were detected in the serum and urine of 2 patients, and the elimination half-life of these metabolites was two- to threefold longer than values seen for cimetidine. During multiple dosing of cimetidine, significant accumulation of cimetidine metabolites may be expected. The reported dose of 15-20 mg/kg/day is adequate in full-term neonates, however, it appears that premature infants and those with renal dysfunction may require lower dosing rates.