Björn Beermann

Pharmacokinetics of hydrochlorothiazide in man

SummaryHydrochlorothiazide (hct) was administered orally in four different doses (12.5, 25, 50 and 75 mg), to eight healthy volunteers. Plasma and urine concentrations of hct were determined by GLC. Maximal plasma levels were found at 1.5–5 h, and averaged 70, 142, 260 and 376 ng × ml−1 respectively. The peak plasma levels and AUC0→9h of hct were highly correlated (p<0.001) with the dose. The decline in the plasma curve was biphasic in those experiments in which the plasma levels of hct could be determined for at least 24 h. The half life of the slower phase lay between 5.6 and 14.8 h. The urinary recovery of hct, which represented the gastrointestinal absorption, averaged 65 to 72 per cent of the dose. The mean renal plasma clearance did not vary with the dose and averaged 319 to 345 ml × min−1. The diuresis during the 10 h after hct 12.5 mg exceeded that after placebo by a mean of 800 ml. The diureses was not increased further after higher doses of hct. The maximal natriuretic effect (+ 100 mmol), too, was found after the 12.5 mg dose. The excretion of potassium, however, rose with increasing doses; the maximal increment, after 75 mg hct, averaged 25 mmol. The excretion of calcium was significantly increased after 50 mg hct (+ 0.6 mmol). The maximal effect on magnesium excretion occurred after 25 mg hct (+ 0.5 mmol). In healthy volunteers there was no correlation between peak plasma level of hct or AUC0→9h and the renal excretion of water and electrolytes.

Kinetics of intravenous and oral pentoxifylline in healthy subjects

The kinetics of a sustained‐release formulation of pentoxifylline were compared with those of a capsule and an intravenous infusion. Ten healthy subjects received each of the oral pentoxifylline formulations (400 mg) three times a day for 9 days in a random crossover fashion. Pentoxifylline (200 mg) was also given intravenously on a separate day. After intravenous pentoxifylline, plasma levels declined in a biphasic manner, with a terminal t½ of 1.63 ± 0.8 hr. Plasma clearance was 1333 ± 481 ml/min and the volume of distribution was 168 ± 82.3 l. Cumulation of pentoxifylline in plasma after repeated dosing was minimal. Plasma levels of the active 5‐hydroxylated metabolite were generally higher than those of the parent drug after both routes of administration. Urinary excretion of two acid metabolites after oral and intravenous dosing indicated almost complete absorption of drug‐related substances from both of the oral formulations, although bioavailability averaged 20% to 30%.

Elimination of furosemide in healthy subjects and in those with renal failure

Furosemide was administered intravenously to 5 healthy volunteers and 15 patients with various degrees of renal failure. Two patients were given the drug orally, The plasma half‐life offurosemide averaged 0.79 hr in the healthy subjects, Although most patients with kidney disease had a prolonged half‐life (t½), up 10 24.58 hr, some with advanced renalfailure had an almost normal t½. The plasma clearance of furosemide, which in the normal subjects averaged 194 ml/min, decreased proportionally with decreasing creatinine clearance, as did the renal clearance, which in the healthy subjects averaged 95 ml/min. There was no correlation between kidney function and the apparent volume of distribution or of non renal clearance. One patient was given 35S‐labeled furosemide intravenously. Although the furosemide plasma t½ was essentially normal, the elimination rate of metabolites was decreased. Unlike that of healthy subjects, the main route of excretion of label was in the feces.

On the fate of furosemide in man

Summary35S-furosemide was administered orally (n=7) or i.v. (n=2) to healthy subjects. The average gastrointestinal uptake estimated by comparison of the urinary recovery of label and the areas under the plasma curves after the two routes of administration was 65%. The half life of radioactivity in the plasma after oral35S-furosemide was 90 ± 17 min (estimated on the slope between 2 and 6 h); the corresponding figure after35S-furosemide i.v. was 47–53 min (slope 0.5–4 h). There was probably a slower phase after 4–6 h. Fractionation of labelled material in urine from two subjects demonstrated that approximately two thirds of the label recovered at 24 h had the same chromatographic properties as furosemide. A major part of the metabolite(s) was probably furosemide glucuronide. There was no evidence that 4-chloro-5-sulfamoylanthranilic acid was formed in man. The total urinary recovery of label (5–7 d) after oral and intravenous administration was 55.1±3.2 (mean±SD) and 82–84%, respectively. After35S-furosemide i.v., 6–9% of the label was recovered in faeces, and it could not be accounted for solely by biliary excretion of furosemide.

Antihypertensive effect of various doses of hydrochlorothiazide and its relation to the plasma level of the drug

SummaryNine previously untreated hypertensive patients (WHO Stage I and II) were given hydrochlorothiazide (hct) 12.5, 25, 50 and 75 mg for two weeks after an initial four week period of placebo treatment. Blood pressure recordings were made casually and after 30 min rest in lying, sitting and standing positions. Plasma concentrations of the drug were measured by GLC. A significant decrease in BP was seen during treatment with hct 12.5 mg except in the casual standing position. Doubling of the dose twice produced very little further decrease in BP. The mean steady state concentration was 111 ng · ml−1 during treatment with hct 75 mg. A linear relationship was found between the plasma concentration of hct at 0 and 5 h and the various dose levels of hct. No relation was found between plasma concentration and reduction in blood pressure.

Kinetics and dynamics of furosemide and slow‐acting furosemide

Bioavailability and dynamics of a sustained‐release preparation of furosemide (FR, 60 mg) were compared with those of a conventional tablet (F, 40 mg). The preparations were given to 12 healthy subjects in a study of crossover randomized design once daily for a week. FR absorption was substantially delayed and the uptake of furosemide was about 75 % of that from F, despite the larger dose administered. F induced a brief, intense diuresis and excretion of Na+, K+, and Cl−, both during short‐ and long‐term administration. There was no such peak after FR. Total diuretic and saluretic effects did not differ between the two preparations, despite the lower bioavailability of FR. It is suggested that this discrepancy might be caused by transient supramaximal urinary levels of furosemide after F, whereby not all of the drug can exert an effect.

Delayed tolerance to furosemide diuresis. Influence of angiotensin converting enzyme inhibition by lisinopril.

The role of the renin-angiotensin-aldosterone system in the development of tolerance to the diuretic effect of furosemide was investigated in 12 healthy male volunteers. Furosemide in a dose of 40 mg daily for one week had a brisk acute diuretic effect, but did not lead to dehydration, hyponatremia or fall in blood pressure. The reason for this was a reduction in sodium excretion between doses (rebound effect) and a decrease in sensitivity to furosemide from day 1 to day 7. The latter phenomenon is referred to as delayed tolerance to furosemide. Inhibition of angiotensin converting enzyme with lisinopril 20 mg daily did not change the renal furosemide excretion rate, the renal sensitivity to furosemide or the tolerance development. Thus, delayed tolerance to furosemide diuresis was not related to dehydration or activation of the renin-angiotensin-aldosterone system. Other mechanisms, probably intrarenal, will have to be looked for.

Coupling between renal tubular secretion and effect of bumetanide.

The relationship between renal tubular secretion of bumetanide and its saluretic effect was studied in six healthy subjects before and after probenecid (1 gm IV). Bumetanide was determined in serum and urine by HPLC. Continuous intravenous infusion of bumetanide (200 μg/hr) gave an average diuresis at steady state of 15 ± 3 ml/min. Corresponding plasma concentration, urinary excretion rate, and renal clearance of bumetanide averaged 14.3 ± 2.3 ng/ml, 64 ± 31 μg/30 min, and 145 ± 59 ml/min. After probenecid there was a marked change in bumetanide kinetics. Average plasma concentration rose to 41.7 ± 8.1 ng/ml, whereas renal clearance and urinary excretion rate fell to 15.1% and 29.5% of control. There was also a concomitant decrease in diuresis and saluresis to 47% and about 40% of control. Probenecid also reduced the renal clearance of para‐aminohippurate and inulin to 67% and 75% of control. Since the fractional water and sodium chloride excretion was also reduced about 33 % and 42%, it is concluded that a large part of the diuretic effect of bumetanide depends on its active tubular secretion. As with furosemide and piretanide, bumetanide diuresis is elicited from the luminal side of the human nephron.

Enhancement of the gastrointestinal absorption of hydrochlorothiazide by propantheline

SummaryHydrochlorothiazide 75 mg was given twice p.o. to fasting subjects. In the second study they had been pretreated with propantheline 60 mg. Plasma and urine concentrations of hydrochlorothiazide were determined by GLC. Pretreatment with propantheline on average delayed the maximal plasma level of hct from 2.4 to 4.8 h (p<0.05); and the total urinary recovery of hydrochlorothiazide by 48 h was increased from 49.3 mg to 66.9 mg (p<0.005). It was concluded that propantheline increased substantially the absorption of the diuretic.

Bioavailability of two hydrochlorothiazide preparations

SummaryEight healthy volunteers received hydrochlorothiazide 75 mg as Dichlotride and Esidrex. Maximal plasma levels were significantly (p<0.05) higher after Dichlotride than Esidrex, 512±189 and 376±70 ng/ml, respectively. However, the bioavailability of the two brands of hydrochlorothiazide did not differ significantly as judged by comparison of the AUC0→9h and AUC0→∞, and the urinary recovery of hydrochlorothiazide during 48 hrs.