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The plasma pharmacokinetics of idarubicin (4-demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half-life of 12.9 +/- 6.0 h (mean +/- s.d.), clearance 98.7 +/- 47.3 1 h-1 m-2 and volume of distribution 1533 +/- 536 1 m-2. A bi-exponential equation corresponding to a two compartment open model best fitted the data. Half-life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/- 0.20 (mean +/- s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half-life of idarubicinol was not significantly different after i.v. (63.1 +/- 28.2 h) and oral (45.8 +/- 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity. [ABSTRACT FROM AUTHOR]

Oxprenolol in an Oros 8/130 sustained release osmotic pump system (equivalent to 120 mg oxprenolol hydrochloride in a conventional formulation and releasing 8 mg h-1) was given to eight normal young subjects (mean age 23 years) and eight elderly hypertensive patients (mean age 77 years). The plasma concentration-time profiles of oxprenolol were determined over 32 h using gas liquid chromatography after the initial dose and following seven doses. The elderly patients had a significantly higher AUC and maximum plasma oxprenolol concentration following both the first and final doses studied. It is unlikely that this difference is due to a prolonged absorption phase in the elderly patients. Reduced drug clearance seems the most probable explanation. [ABSTRACT FROM AUTHOR]

The plasma cortisol response to 0.25 mg tetracosactrin given by intramuscular injection was suppressed by nine oral doses of 200 mg ketoconazole given 12 hourly to nine normal female subjects. No effect was noted following a single 200 mg oral dose of ketoconazole. This suppressive effect was reversible within at least 5 days of discontinuation of ketoconazole. [ABSTRACT FROM AUTHOR]

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.

We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests (AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not be optimal.

The effect of simultaneous oral administration of 20, 40, or 80 mg domperidone on the pharmacokinetics of an oral 500 mg dose of levodopa was studied in eight normal women. No significant differences in maximum plasma levodopa concentration, the time of its attainment, or the area under the plasma levodopa concentration versus time profile occurred. Domperidone significantly reduced the incidence of adverse gastrointestinal effects due to levodopa administration.

Flusoxolol (Ro 31-1411) is the pharmacologically active optical isomer of Ro 31-1118, a potent cardioselective beta-adrenoceptor antagonist with partial agonist activity. It was given to 6 healthy volunteers in a single dose, 40 mg, and then in multiple doses, 40 mg daily for 8 days. Plasma concentration data were best described by a linear two-compartment pharmacokinetic model with first order absorption, and the results confirmed linear kinetics. Pharmacokinetic data for flusoxolol were comparable to those for the racemate Ro 31-1118.