Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174.

Theophylline tissue partitioning and volume of distribution in normal and dietary-induced obese rats.

Theophylline tissue distribution was examined in normal and dietary-induced obese Sprague-Dawley rats following constant infusion to steady-state. Theophylline distribution was linear among all tissues and uniform throughout body water spaces. The apparent distribution coefficient, Kd,app (tissue: serum concentration) ranged from 0.55 to 0.69 for all lean tissues, but averaged 0.08 in fat. Obese rats had a consistently higher Kd,app in several tissues including muscle, heart, and liver caused by reduced (from 42 to 33 per cent) serum protein binding. Muscle slice uptake of theophylline from buffer was similar in normal and obese animals, confirming serum binding as the factor altering Kd,app. The conceptual and applied bases of calculating and measuring steady-state volume of distribution (VSS) by various methods were explored. The physiological perturbations of theophylline VSS by obesity can be accounted for by alterations in serum binding and expanded lean and fat tissue masses, rather than changes in tissue partitioning.

Pharmacokinetics of tritiated water in normal and dietary-induced obese rats.

Tritiated water disposition was characterized in normal and dietary-induced obese rats to assess pharmacokinetic concerns in calculating water space and estimating body fat. A monoexponential decline in serum tritium activity was observed in both groups of rats, thus facilitating use of various computational methods. The volume of distribution and the total clearance of tritium in obese rats were larger than in normal rats because of the increased body weight. The values of water space (volume of distribution) estimated from moment analysis or dose divided by serum tritium activity at time zero (extrapolated) or at 2 hr were all similar. Thus, obesity does not alter the distribution equilibrium time and distribution pattern of tritium, and the conventional 2-hr single blood sampling after intravenous injection is adequate to estimate the water space of normal and obese rats.

Pharmacokinetics of theophylline in hepatic disease.

The disposition of theophylline was examined in eight male cirrhotic (six proven by biopsy) patients without heart failure. An oral dose of 100 mg of theophylline per square meter of surface area was administered, and samples of serum and saliva were collected from 0 to 60 hours and were assayed by high-pressure liquid chromatographic techniques. Controls were 57 young normal subjects and 25 age-matched patients. The body clearance of theophylline in cirrhotic patients was low, averaging 18.8 +/- 11.3 ml/kg/hr (+/- SD) vs 53.7 +/- 19.3 and 63.0 +/- 28.5 ml/kg/hr in the control patients and the normal subjects, respectively. The half-life of theophylline in cirrhotic patients was prolonged wiht a mean of 28.8 +/- 14.3 hours compared to 6.0 +/- 2.1 hours in normal subjects. Patients with cirrhosis proven by biopsy had significantly lower values for body clearance and longer half-lives than subjects without biopsies. The values for body clearance correlated well with the serum level of bilirubin (r = -0.81) and the serum level of bile acids (r = -0.81). The slow and variable metabolism in cirrhotic patients necessitates a reduction in the maintenance dosage of aminophylline to 0.20 to 0.45 mg/kg/hr and monitoring of the serum level during therapy.