Percutaneous penetration kinetics of nitroglycerin and its dinitrate metabolites across hairless mouse skin in vitro.

The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 +/- 1.5 nmol cm-2 hr-1) was significantly greater (P less than 0.05) than those of 1,2-GDN (0.81 +/- 0.54 nmol cm-2 hr-1) and 1,3-GDN (0.72 +/- 0.20 nmol cm-2 hr-1). The corresponding permeability coefficient (rho) for GTN (20 +/- 3 x 10(-3) cm hr-1) was significantly larger than the corresponding values for 1,2-GDN (1.4 +/- 0.9 x 10(-3) cm hr-1) and 1,3-GDN (1.2 +/- 0.4 x 10(-3) cm hr-1), which were statistically indistinguishable (P greater than 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (Ks) values of the compounds. The apparent partition parameters, defined as kappa = Ks.h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 +/- 2.5 x 10(-2) cm for GTN and 1.91 +/- 1.07 x 10(-2) and 1.81 +/- 0.91 x 10(-2) cm for 1,2- and 1,3-GDN, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A quantitative method of evaluating the diuretic response to furosemide in rats.

Furosemide effects are usually evaluated by measuring the urinary excretion rate of Na+ (UVNa) in humans. In the present study, however, UVNa showed a nonlinear relationship with urine flow rate after intravenous injection of furosemide in rats. In contrast, when the urinary excretion rate of (Na+ + K+) (UVNa + K) was plotted against the urine flow rate, a linear regression line was observed, with small interindividual variations in normal rats and in rats with uranyl nitrate-induced acute renal failure (ARF). Piretanide, a loop diuretic, also showed a similar relationship, while other types of diuretics revealed different slope values for the relationship. Although the urinary excretion rate of Cl- (UVCl) vs UVNa + K is expected to show a linear relationship in normal rats, the correlation coefficient of the linear regression line was smaller than that of the urine flow rate vs UVNa + K. Further, the slope of UVCl vs UVNa + K was slightly different in ARF rats. Therefore, UVNa + K provides a better quantitative measure of diuretic response to loop diuretics than UVNa or UVCl.

Urinary excretion and diuretic action of furosemide in rats: increased response to the urinary excretion rate of furosemide in rats with acute renal failure.

A urinary excretion-response curve representing the urinary excretion rate of furosemide versus the urinary excretion rate of (Na+ + K+) was used to analyze furosemide action in rats with uranyl nitrate-induced acute renal failure (ARF) with and without dopamine coadministration. Urinary excretion of furosemide, but not its serum concentration, was the determinant for the diuretic action of furosemide. Increased diuretic response was observed in ARF rats, although the total diuretic response and urinary recovery of furosemide within 2 hr decreased. Dopamine enhanced furosemide-induced diuresis in ARF rats in terms of the total urine output and urinary electrolyte excretion, although the urinary excretion-response curves were not different. This enhancement by dopamine was found to be caused by the augmented urinary excretion of furosemide and the increased response to this drug in ARF rats. These findings suggest the contribution of decreased concentrating ability along the nephron and/or increased sensitivity of cells at the site of action to this drug.

Increased diuretic response to furosemide in rats with glycerol-induced acute renal failure.

To clarify the diuretic response to furosemide in a diseased state, the urinary excretion of furosemide, water, and electrolytes was examined after a single intravenous injection of furosemide in control rats and rats with mild acute renal failure (ARF) induced by glycerol. The urinary recovery of furosemide was similar in the control and ARF rats. However, the diuretic response to furosemide was increased in ARF rats compared with control rats. Although the relationship between the urine flow rate (UFR) and the urinary excretion rate of (Na+ + K+) (UV Na + K) was the same in both groups, the urinary excretion rate of K+ (UV K) was decreased in ARF rats. The concentrating ability in ARF rats was also decreased compared with that in control rats. By infusion of aldosterone in ARF rats, both UV K and the concentrating ability were increased and the diuretic response to furosemide was decreased, whereas the relationship between UFR and UV Na + K was not changed. Therefore, it is concluded that the increased diuretic response to urinary excretion of furosemide in ARF rats may be caused, at least in part, by the decreased concentrating ability along the nephron.