Analysis of isobutyl nitrite inhalant in rat and human blood: application for pharmacokinetic investigations.

Organic nitrites have been used therapeutically for the treatment of angina pectoris and as diagnostic agents for the evaluation of cardiac heart murmurs. In addition, these highly volatile vasodilators are being used as inhalant drugs of abuse. We developed a gas chromatographic assay using electron capture detection for the analysis of a representative nitrite inhalant, isobutyl nitrite (ISBN), in rat and human whole blood. Unconventional sampling and processing techniques were required because of the high volatility and chemical instability of nitrites in biological fluids. Our method produced a mean recovery of ISBN from rat blood of about 86% over a concentration range of 1.0 to 400 ng/ml. The inter-day coefficient of variation was below 15% at the lowest quantifiable concentration of 1 ng/ml ISBN in rat blood. In this report, we applied the analytical method to obtain new pharmacokinetic information about ISBN. Results show that rats inhaling 900 ppm ISBN for 45 min produced steady-state blood concentrations of about 290 ng/ml, and a rapid elimination half-life of 1.4 min.

Endothelial nitric oxide generating enzyme(s) in the bovine aorta: subcellular location and metabolic characterization.

The metabolic production of nitric oxide (NO) from bovine endothelial homogenates and subcellular fractions was examined. NO was quantified using a sensitive and specific ozone redox-chemiluminescence detector. Endogenously produced NO was detected in the headspace gas of bovine vascular endothelial homogenates supplemented with superoxide dismutase and an NADPH regenerating system, which had been incubated at 0 degrees C for 3 hr. An identical system incubated at 37 degrees C for 3 hr did not produce NO. Both superoxide dismutase and an NADPH regenerating system were required for observing endogenous NO production from endothelial homogenates. Among the various endothelial subcellular fractions tested, only the 1000 x g supernatant manifested significant generation of endogenous NO. Addition of 1.4 mM L-arginine (but not D-arginine, L-citrulline or L-lysine) resulted in significant enhancement of NO production from the 15,500 and 210,000 x g pellet fractions. L-arginine did not stimulate NO production from either homogenates or subcellular fractions of coronary vascular smooth muscle cells. Exogenously added calcium or magnesium was not required for NO generation in the 210,000 x g pellet stimulated with L-arginine, whereas L-canavanine (1.4 mM) and SKF 525-A (0.1 mM) significantly inhibited NO production with this preparation. Analysis of the enzyme marker data from various subcellular fractions suggests that the endothelial NO-generating enzyme system is membrane-bound and might be associated with the plasma membrane.

Haemodynamic effects of combined oral nifedipine and sublingual nitroglycerin in patients with chronic stable angina.

We examined the pharmacokinetics of nifedipine after acute and sustained oral therapy and the potential haemodynamic interaction between nifedipine and sublingual nitroglycerin in nine patients with chronic stable angina. Nifedipine pharmacokinetics after a single oral dose and sustained dosing (three times daily for five days) were not significantly different. Single dose nifedipine produced a statistically significant decrease in standing and supine systolic and diastolic blood pressures when compared to placebo. A significant decrease in the supine systolic pressure was observed after sustained nifedipine therapy. Except for this change, other hypotensive effects of nifedipine after sustained therapy were not different to those of placebo, in spite of persistent plasma nifedipine concentrations after repeated dosing. There were no observable correlations between nifedipine haemodynamics and pharmacokinetics in these patients, nor were there any significant haemodynamic interactions between sublingual nitroglycerin with either acute or sustained nifedipine treatment. The transient haemodynamic effects of sublingual nitroglycerin were not potentiated by either acute or sustained nifedipine therapy.

The effects of dietary calcium on lead absorption, distribution, and elimination kinetics in rats.

A pharmacokinetic analysis of lead absorption, distribution, and elimination was conducted in rats maintained on calcium-deficient, control, and calcium-supplemented diets. Dietary calcium affected lead disposition in a number of ways. Systemic lead clearance after a 10-mg/kg intracardiac lead dose was approximately 25% lower than control in rats administered dietary calcium supplements. Intestinal absorption of 10 mg/kg po lead doses was not affected by the calcium supplements. In rats maintained on a calcium-deficient diet, systemic lead clearance was estimated to be 40% less than control. The apparent volume of lead distribution was increased. The apparent systemic availability of 1-, 10-, and 100-mg/kg oral lead doses was three- to fourfold greater than control in calcium-deficient rats. The percentage absorption was dose-dependent in control and calcium-deficient rats. The observed changes in lead absorption and systemic clearance associated with the calcium-deficient diet represent synergistic effects that could elevate blood lead accumulation and thus potentially influence susceptibility to lead toxicity.

Effects of L-cysteine, L-cysteine derivatives and ascorbic acid on lead excretion in rats.

Urinary and fecal excretion of lead in rats were compared after intravenous administration of L-cysteine and a number of its derivatives. In terms of increasing total lead excretion, L-cysteine ethyl ester was about half as effective as D-penicillamine, whereas L-cysteine and all other derivatives tested were only marginally effective. Interestingly, L-cysteine ethyl ester appeared to increase lead depletion mainly through biliary excretion. This compound may, therefore, have lower renal toxicity than other chelating agents which promote lead excretion principally by increasing urinary elimination. Dietary supplements containing 1% cysteine, 1% ascorbic acid of 1% of both substances did not dramatically increase lead elimination.