Biomedical subjects
B Odlind
Publications and source records attributed to B Odlind.
Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods.
The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healthy volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations greater than 4 micrograms/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 micrograms/ml (range 3.1-9.5 micrograms/ml); the minimum value was 1.5 micrograms/ml (range 0.6-2.9 micrograms/ml). The mean AUCss was 77 micrograms/ml X h and the mean plasma clearances was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7-15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 micrograms/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 mumol/l, probably due to competitive inhibition of the tubular secretion of creatinine.
Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis.
Furosemide 40 mg was administered to 8 healthy subjects as an i.v. bolus dose, as 1 tablet in the fasting state, and as 1 tablet and a solution after food intake. The i.v. data gave a total body clearance of 162 +/- 10.8 ml/min and a renal clearance of 117 +/- 11.3 ml/min; the volume of distribution at steady state was 8.3 +/- 0.61. Oral administration gave a bio-availability of the tablet (fasting) of 51%. Food intake slightly reduced the bioavailability, but not to a significant extent. There was no significant difference in availability between the tablet and the solution. Moment analysis gave a mean residence time after the i.v. dose, MRTi .v., of 51 +/- 1.5 min. The mean absorption times (MAT) for all oral doses were significantly longer than the MRTi .v., indicating absorption rate-limited kinetics of furosemide. On average, food delayed the absorption by 60 min. The MAT for the tablet in the postprandial state was significantly longer than for the solution, indicating dissolution rate-limited absorption of the tablet.
Site and mechanism of the action of diuretics.
The mechanism of action of diuretics can be established by studying the molecular mechanism of action, the site of action within the nephron, and the relationship between the pharmacokinetics of the diuretic and its effect. The molecular mechanism of action is known for diuretic agents such as acetazolamide (carbonic anhydrase), theophylline (phosphodiesterase), digitalis glucosides (Na-K-ATPase), spironolactone (aldosterone antagonism) and dopamine (specific receptors?). The "receptor" for the clinically most important diuretics, i.e. loop diuretics, thiazides, and other potassium-sparing diuretics is, however, unknown. It appears from recent studies of the ion transport in the diluting segment that there probably is a sodium-chloride co-transport in this segment and that loop diuretics specifically inhibit the active chloride transport. The main site of diuretic action is well established for the different groups of diuretics: carbonic anhydrase inhibitors act on the proximal tubulus, loop diuretics on the diluting segment, thiazides on the cortical diluting segment/distal tubulus, and potassium-sparing agents on distal tubulus/collecting ducts. Moreover, some diuretics have additional tubular sites of action. It is also important to realize that other effects of diuretics, e.g. inhibition of the tubuloglomerular feedback mechanism or renal and extra-renal hemodynamic effects, can modify the tubular diuretic effect. Finally, the renal handling of diuretics is of importance to the diuretic effect by determining the concentration of the drug at the "receptor" sit (s). It is emphasized that knowledge of the different aspects of the mechanisms of action of diuretics is a prerequisite for rational use of diuretics, clinically as well as experimentally.
Peritubular uptake of 125I-insulin in the avian kidney.
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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 micrograms/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 micrograms/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.
Total serum IgE in uremia and after renal transplantation.
Uremic patients on maintenance hemodialysis, but without clinical evidence of atopy or diabetes mellitus, had serum levels of total IgE significantly lower than in healthy controls matched for age and sex. Patients with uremia due to diabetic nephropathy had higher IgE levels than the reference group. No correlation was found between total IgE levels and length of dialysis treatment. After renal transplantation, the IgE levels decreased on average to 31% of the pretransplant values over a 60-day observation period. Bacterial or viral infections or episodes of kidney rejection had no apparent influence on the IgE synthesis in the patients with transplant. No correlation was detectable between pretransplant IgE levels and six-month survival of the kidney graft. The low IgE concentrations in uremia are suggested to reflect altered T-cell regulation of the IgE production. The raised IgE levels in diabetic patients could not be explained by specific reagins against insulin, but may have reflected an influence of abnormal carbohydrate metabolism on IgE synthesis. The fall in IgE levels following transplantation is proposed to be attributable to the combined corticosteroid-azathioprine treatment.
Determinants of access of diuretics to their site of action.
For consideration of the determinants of access of diuretics to their site of action to be meaningful, one must understand molecular modes of action of diuretics and the anatomic site of effect along the nephron in addition to determinants of the renal handling of diuretics. Although the molecular mode of action is known for a number of drugs, such as the inhibition of carbonic anhydrase by acetazolamide, that for loop diuretics remains obscure. Sites of diuretic action along the nephron have been well delineated through collation of results from in vitro and in vivo techniques in a variety of species. Loop diuretics clearly block chloride reabsorption throughout the thick ascending limb of the loop of Henle. Access of diuretics to their renal tubular sites of action varies among drugs. Important determinants are plasma protein binding, active tubular secretion, nonionic diffusion, and intrarenal metabolism.
Diuretic effect and pharmacokinetics of tizolemide in subjects with normal and decreased renal function.
Tizolemide, a new sulphonamide diuretic, has alkaline properties and is cleared by a tubular transport system which differs from the PAH-excreting system which transports thiazide diuretics. The effect of this drug on the excretion of sodium and other electrolytes, and its pharmacokinetics, were evaluated in 5 healthy volunteers and in 10 patients with renal disease who had GFRs ranging from 5-98 ml/min. The saluretic effect of tizolemide was compared with that of placebo. The increase in sodium and chloride excretion after a single dose of 50 mg i.v. was clearly dependent on residual renal function but could be observed in all except one patient. It remains to be assessed whether a full diuretic effect can be achieved in patients with renal insufficiency if higher doses are used. The plasma half-life was 3.0 hours in healthy subjects but increased in patients with renal insufficiency to a maximum of 52 hours. In normal subjects total plasma clearance (611 ml/min) mainly depended on the renal clearance (564 ml/min) which decreased in proportion to GFR, whereas non-renal clearance remained unchanged. The large apparent volume of distribution of the drug (166 l/1.73 m2 BSA) did not increase significantly in uremia. Clinical trials with this drug in patients with reduced renal function must take into account the expected prolongation of its half-life.
Renal tubular secretion of piretanide and its effects on electrolyte reabsorption and tubuloglomerular feedback mechanism.
Piretanide [HOE 118; 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoxylbenzoic acid] is a new diuretic with a saluretic effect similar to that of furosemide. The present experiments were undertaken to investigate if transport of piretanide into the tubular lumen determines the diuretic response and what effect piretanide has on the tubuloglomerular feedback control and loop of Henle electrolyte transport. To study the first question, five healthy subjects were investigated. Piretanide, inulin and p-aminohippuric acid were continuously infused. After equilibration, 1 g of probenecid was given which reduced the tubular secretion of piretanide to one-sixth of control level. The reduction in diuresis was 41.4% while it was 59.5, 63.9 and 45.8% for the urinary excretion of chloride, sodium and potassium, respectively. In a second series of experiments in rats a proximal tubular stop-flow pressure response at increased distal delivery of fluid was measured when Ringer's solution, Ringer's solution plus furosemide (10(-4) M) or bumetanide (5 X 10(-5) M) or piretanide (10(-4) M and 5 X 10(-5) M) was added to the tubular perfusion solution. The results indicate that the feedback could be completely blocked by any of these diuretics. The fluid absorption in the loop of Henle was studied in separate experiments and the addition of piretanide (10(-4) M) greatly reduced chloride and absolute fluid absorption from this nephron segment. The present results indicate that tubular secretion of piretanide is important for the diuretic response and that piretanide inhibits the fluid absorption in the loop of Henle and the tubuloglomerular feedback control which would otherwise blunt the diuretic response with a reduction in glomerular filtration rate.
Effects of bendroflumethiazide on urate metabolism during treatment of patients with renal stones.
Treatment with bendroflumethiazide (2.5 mg, twice daily with potassium supplements) in 63 patients with calcium-containing renal stones for a minimum period of 1 year (average duration of treatment 2.6 years) increased the serum urate values in all patients with an average of 90 mumol./l. (conversion factor: 1 mmol. urate = 183 mg.). Despite this the mean urinary urate excretion was unchanged. In the individual patient a systematic effect of therapy was evident since in patients with low pretreatment values the thiazide increased the urate output while in those with the highest levels before therapy it caused a reduction. In most patients there was a reduction of the urate clearance during therapy, which was most evident in those with the highest pretreatment clearance values. In patients with incomplete types of renal acidification defects the same effects were seen on urate metabolism during thiazide treatment as in the other, idiopathic, stone formers. Although the possible role of urate in calcium stone formation has not been definitely settled this study shows that thiazides do not cause hyperuricosuria and hence their beneficial effects on calcium excretion are not counteracted.
Renal tubular secretion and effects of chlorothiazide, hydrochlorothiazide and clopamide: a study in the avian kidney.
The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is a sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.
Extractive alkylation of 6-mercaptopurine and determination in plasma by gas chromatography-mass spectrometry.
An analytical procedure was developed for the determination of 6-mercaptopurine in plasma. Owing to the polar character and low plasma concentration of the compound, extraction and derivatization was carried out directly from the plasma sample by extractive alkylation. Determination was made using gas chromatography-mass spectrometry with multiple-ion detection. Conditions with respect to the rate of formation and the stability of the derivative formed in the extractive alkylation step were evaluated. The selectively of the method to azathioprine and to metabolites was thoroughly investigated. No 6-mercaptopurine was formed from azathioprine added to water or plasma and run through the method. The method enables the detection of 2 ng of 6 mercaptopurine in a 1.0-ml plasma sample. Quantitative determinations were done down to 10 ng/ml 6 mercaptopurine in plasma.
Tubular secretion and effects of tienilic acid in the hen.
The relationship between renal tubular secretion of the uricosuric diuretic tienilic acid (10 or 30 microgram/kg per min) and its saluretic effects was determined using a modified Sperber technique. A true tubular excretion fraction (TTEF) or 29.9 +/- 4.1% (mean +/- S.D.) was found for tienilic acid, a value significantly (P less than 0.001) reduced by novobiocin to 3.3 +/- 2.8%. This demonstrates active tubular secretion of the diuretic by an organic anion transport system in the hen kidney. Infusion of the diuretic into one leg vein caused a marked ipsilateral excess excretion of chloride, sodium and potassium; these effects were significantly reduced by novobiocin. Thus, in the hen a significant part of the saluretic effect of tienilic acid depends on the active secretion of the drug by tubular cells, as has previously been found for three loop diuretics i.e. ethacrynic acid, furosemide and piretanide. In analogy with these, it is suggested that the saluretic effect of tienilic acid is evoked mainly from the luminal side of the avian nephron. At an infusion rate of 20 microgram/kg per min of tienilic acid, a marked saluresis occurred; there was, however, no effect on the urinary urate excretion.
Renal tubular secretion and effects of the alkaline diuretics amiloride, tizolemide (Hoe 740) and 2-aminomethyl-4(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447).
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Autoradiographic localization of 35-S-furosemide at different stages of its renal excretion.
The renal localization of 35-S-activity was studied by autoradiography at different times (1/2 min intervals) following the rapid injection of a bolus of 70 micrograms 35-S-furosemide into the renal portal system of hens. After removal, both kidneys were freeze-sectioned, freeze-dried and subjected either to apposition autoradiography according to Ullberg or to microautoradiography. There was extensive labelling over cortical areas of the ipsilateral kidney, in the periphery of lobuli, the site of proximal tubular cells. This labelling was maximal at 1 and insignificant already at 4 min post injection. At this time, however, there was a distinct patchy labelling corresponding to collecting ducts. At 7 min post-injection no specific labelling was found. The findings suggest that furosemide in the peritubular blood is accumulated in proximal tubules, rapidly transferred (tubular secretion) to their lumina and carried distally by the tubular fluid, subsequently resulting in high concentrations of the diuretic in the lumina of collecting ducts. Thus the findings are in keeping with the view that active tubular secretion of furosemide in the hen contributes significantly to a high luminal concentration of the drug in more distal parts of the tubules, the likely site of diuretic action.
Low-dose steroids in renal transplantation: one year experience in Uppsala.
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Pharmacokinetics of azathioprine and 6-mercaptopurine: methodological aspects and preliminary results in uremic patients.
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