Pharmacokinetics of metformin after intravenous and oral administration to man

Summary The kinetics of¹⁴C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of flip-flop type for oral metformin.     

Pharmacokinetics of cimetidine and its sulphoxide metabolite during haemodialysis

Summary A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74±0.12 and 0.76±0.08 µg/ml, and after dialysis for 4h 1.08±0.10 and 0.51±0.08 µg/ml, respectively (mean ± SE). The average haemodialysis clearance (Cl_HDa) of cimetidine during dialysis was 46–92ml/min at a dialysate flow rate of 320ml/min and blood flow rates in the 6 patients between 160–240ml/min. The mean Cl_HDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49–148ml/min. During haemodialysis the mean plasma elimination half-life (t_1/2) of cimetidine was 3.24h (range 2.08–5.08) and of the sulphoxide metabolite 9.49h (range 4.70–14.39). There was a significant relationship between the elimination rate constant () and Cl_HDa of the sulphoxide metabolite (p<0.01), but no such relationship was found between and Cl_HDa of cimetidine. However, there was a tendency to a relationship between of cimetidine and the capacity to metabolise the drug, expressed as the ratio between the plasma concentrations of the sulphoxide metabolite and cimetidine after dialysis for 4h. These ratios ranged between 0.23–0.76, and the lowest ratio was seen in the patient with the lowest value of cimetidine. Thus, the large variations in the plained by differences in their capacity to metabolise the drug. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9–31.8), which was 9.0–15.9% of the given dose. Between 12.2–21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.     

Der Einfluß der Nierenfunktion auf die Kontrastmittelelimination nach Infusionspyelographie

Zusammenfassung Bei 25 Patienten mit normaler und unterschiedlich eingeschränkter Nierenfunktion infolge beidseitiger parenchymatöser Nierenerkrankungen wurde die Elimination von Methylglucamin-Iothalamat bis 3 Tage nach der Infusionspyelographie (3 ml Conray FL^®/kg Körpergewicht) untersucht. — Die Kontrastmittelkonzentration im Plasma fiel exponentiell entsprechend einer zusammengesetzten Ausgleichsfunktion ab. Der Abfall wurde mit zunehmender Niereninsuffizienz geringer und die Halbwertzeit länger. Die Korrelation zwischen Halbwertzeit im Intravasalraum und glomerulärer Filtrationsrate (GFR = Inulinclearance) war signifikant. Die Halbwertzeit betrug bei 11 Patienten mit normaler Nierenfunktion (GFR 114±19 ml/min/1.73 m²) 1.1 Std und bei 7 Patienten mit eingeschränkter Nierenfunktion (GFR 37±6 ml/min/1.73 m²) 3 Std bzw. stark eingeschränkter Nierenfunktion (GFR 11±4 ml/min/1.73 m²) 8.7 Std. — Die kumulierende renale Kontrastmittelausscheidung in Prozent der infundierten Menge stieg exponentiell. Die Ausscheidung wurde mit zunehmender Einschränkung der Nierenfunktion geringer. Die Hälfte der Gesamtausscheidung wurde bei normaler Nierenfunktion in 1.7 Std, bei eingeschränkter in 4.6 Std und bei stark eingeschränkter Nierenfunktion in 13.9 Std erreicht. Diese Halbwertzeit korrelierte signifikant mit der glomerulären Filtrationsrate.

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The effect of renal function on the elimination of contrast medium by infusion pyelography

Summary The elimination of the contrast medium meglumine iothalamate (Conray FL^®) was investigated for 3 days after infusion pyelography (3 ml containing 339 mg iodine per kg of body weight) in 25 patients with normal, moderately and severely reduced renal function. — The glomerular filtration rate (GFR = inulinclearance) was normal in 11 patients (114±19 ml/min/1.73 m²), moderately reduced (37±6 ml/min/1.73 m²) and severely reduced (11±4 ml/min/1.73 m²) in 7 patients resp. There was an exponential fall of the plasma level of iothalamate which was analyzed according to a two compartment model. — In the intravascular compartment the half time was 1.1 h in normal renal function, 3 h in moderately reduced renal function and 8.7 h in severely reduced renal function. A significant negative correlation between the half time and GFR was found. The renal excretion fell with reduced GFR. The cumulative excretion rose exponentially and reached within 6 h and 72 h resp. 85.0±5.1 and 94.3±4.4% resp. of the dose given in normal renal function, 55.6±10.2 and 93.2±2.8 resp. in moderately reduced and 24.6±7.1 and 81.3±5.9% resp. in severely reduced renal function. There was a significant negative correlation between the half time of the renal excretion and GFR. This half time was 1.7 h in normal renal function, 4.6 h in moderately reduced and 13.9 h in severely reduced renal function.

     

Pharmacodynamics and pharmacokinetics of oral nitrendipine solution in hypertensive patients with advanced renal failure

Summary Nitrendipine solution 5 mg·ml^–1 in the dose of 5 mg was given orally to 20 patients with chronic renal failure and elevated diastolic blood pressure (110 mmHg), of whom 10 were on maintenance haemodialysis (endogenous creatinine clearance <5 ml·min^–1) and 10 were at the predialysis stage (endogenous creatinine clearance 5–20 ml·min^–1).The aim of the study was to investigate the influence of kidney function and/or dialysis treatment on the pharmacokinetic and pharmacodynamic profile of a solution of nitrendipine and to assess its antihypertensive efficacy.After 10 min there was a significant reduction in blood pressure from 188/113 to 173/100 (patients not dependent on dialysis) and from 197/112 to 161/94 mmHg (patients dependent on dialysis). The maximum fall in blood pressure (approximately 30%) was attained after 90 min in the dialysis patients and after 120 min in the non-dialysis group. Blood pressure increased again about 3 h after the administration of nitrendipine but it was still below baseline after 12 h. The terminal elimination half-life (4.1 h in the dialysis patients and 3.6 h in non-dialysis patients) was similar to that observed in patients with normal renal function. The pharmacokinetics of nitrendipine did not differ between the dialysis and non-dialysis groups. There was a correlation between plasma concentration and the blood pressure reduction. The maximum plasma concentration of nitrendipine was reached after 0.5 h (median) and did not differ between the two groups. The mean maximum plasma concentration was 14.8 g·1^–1 in the study population as a whole, with comparable means in the dialysis (17.3 g·1^–1) and non-dialysis (12.4 g·1^–1) groups.The nitrendipine solution proved to be effective in lowering acutely elevated blood pressure in patients with advanced renal failure and renal hypertension, and was well tolerated. The pharmacokinetics was not affected by renal impairment or by dialysis.     

Pharmacokinetics of acebutolol in patients with all grades of renal failure

Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p<0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p<0.001; NAM: r=0.954,p<0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (_bc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.     

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis

Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.     

Comparison of the pharmacokinetics of diazepam after single and subchronic doses

Summary In seven healthy male volunteers the effects of the pattern of dosing on the pharmacokinetics of diazepam have been studied. A cross-over design was employed that consisted of three parts: a single intravenous dose (0.1 mg/kg), and oral dosing (10 mg/day) for six days followed by an intravenous bolus (0.1 mg/kg) on the seventh day, followed by re-examination of a single intravenous dose after diazepam (D) and its major metabolite desmethyldiazepam (DD) had been completely eliminated. Plasma levels of D and DD were monitored by a specific, sensitive GLC-method. In younger patients (n=5, age 29 – 35 years) the elimination half-life, T_{1/2 ()}, of D was 33.9±10.6 h (mean±S.D.) after the single dose. The control study gave an almost identical result (35.7±12.1). After subchronic dosage in all patients T_{1/2 ()} showed a modest but significant prolongation (paired t-test p<0.01) to 52.9±17.4 h. It was caused by a significant decrease (p=0.016) in total plasma clearance ( ), from 26.0±10.8 ml/min to 18.2±7.0 ml/min. Older patients (age 43–60 years) showed the same phenomenon. Blood/plasma ratios remained constant indicating no change in protein binding. Biliary excretion of D was measured in five patients with a T-tube. Only negligible amounts (0.3–0.4%) of administered D were excreted within 3 days after subchronic dosage, which demonstrates a lack of enterohepatic cycling of D. After multiple administration of D, there was accumulation of DD to levels approximately five times higher than after a single dose. The possibility that the slower elimination of D after subchronic treatment might be caused by DD was also supported by experiments in dogs and rabbits. After pretreating rabbits with DD and maintaining a high DD plasma level, there was prolongation of T_{1/2 ()} from 2.7 h to 5.2 h, with a corresponding decrease of from 101.6 ml/min to 23.4 ml/min. Similar results were obtained in dogs. It is concluded that the disposition of D is altered by subchronic use and may be regulated by the plasma DD concentration.The results were presented in part at the 6th International Congress of Pharmacology, Helsinki, 1975     

Oral absorption of cimetidine and its clearance in patients with renal failure

Summary The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1–52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5–15 ml/min 200 mg every 12 to 8 h, 15–30 ml/min 200 mg every 8 h and 30–52 ml/min 200 mg every 6 h.     

The effects of alpha-adrenoceptor blockade on dopamine-induced renal vasodilation and natriuresis

Summary To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pretreatment with the selective postsynaptic alpha₁-adrenoceptor antagonist prazosin in normal volunteers and in patients with renal disease and moderately impaired renal function.Prazosin (1 mg p. o. every 4 h) in 7 volunteers did not significantly affect baseline values but impaired the response of effective renal plasma flow (ERPF) and filtration fraction (FF) to infusions of dopamine in doses ranging from 0.5 to 8 g/kg per minute and completely abolished the dopamine-induced increase in sodium excretion. In 7 patients with renal disease and a glomerular filtration rate (GFR) ranging from 38–85 ml/min pretreatment with prazosin did not affect baseline ERPF, GFR or FF or their response to dopamine infusion, but sodium excretion and its response to dopamine infusion were reduced (fractional excretion of sodium at baseline 1.78 without and 0.89 with prazosin pretreatment).We conclude that alpha₁-adrenoceptor blockade with prazosin abolishes the effects of exogenous dopamine on sodium excretion in normal man. Prazosin also impairs the renal vasodilatory action of dopamine. However, the effect on sodium excretion is not directly related to inhibition of dopamine-induced renal vasodilation since in patients with renal disease prazosin also markedly reduces sodium excretion but does not influence the renal hemodynamic effects of dopamine. Send offprint requests to A. J. Smit at the above address     

Effect of haemodialysis on the pharmacokinetics of cetirizine

Summary The pharmacokinetics of Cetirizine, a histamine H1-receptor antagonist, were investigated in five renal failure patients undergoing chronic haemodialysis therapy. The patients received one 10 mg cetirizine dihydrochloride capsule 3 h before haemodialysis.Concentrations of cetirizine in serum and dialysate were determined by HPLC. The maximum serum cetirizine concentration and the time to reach that maximum were 285 g·1^–1 and 2.0 h, respectively. The terminal disposition half-life of cetirizine in these patients was 19.3 h.The haemodialysis clearance of cetirizine was 14.0 ml · min^–1. Although this is approximately 33% of the apparent total body clearance of cetirizine in subjects with normal renal function, the fraction of the dose removed by dialysis was only 9.4%. Thus, since haemodialysis does not produce a clinically significantly alteration in cetirizine elimination, no supplemental dose should be necessary after dialysis.     

The effect of renal function on the pharmacokinetics of ranitidine

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied.Renal function was assessed in each patient by ⁵¹Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC.Patient groups with renal impairment had significantly increased AUC and t_1/2 with corresponding decreases in CL_p and _z when compared with normal subjects. There was also a significant increase in t_max but not in C_max. There was a high linear correlation between the degree of renal impairment and ranitidine clearance.In patients with GFR 20 ml min^–1, the AUC mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min^–1, the average AUC ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR 20 ml min^–1.     

Pharmacokinetics of atenolol in relation to renal function

Summary The pharmacokinetics of atenolol were determined following acute intravenous and chronic oral administration to 20 subjects with a glomerular filtration rate (GFR) between 5 and 113 ml/min. Plasma levels in a further 5 patients on haemodialysis were measured after intravenous treatment. The mean half life of elimination increased from 5.9 h in patients with normal renal function to 42.1 h in preuraemic patients (GFR <10 ml/min) following a single i. v. dose. The half life of elimination following chronic oral administration was not significantly different. Mean peak plasma concentrations increased from 540 ng/ml in patients with normal renal function to 1493 ng/ml in preuraemic patients following chronic oral treatment with 100 mg/day. The mean half life of elimination during a single haemodialysis treatment was 4.3 h. In patients with a GFR >30 ml/min the normal daily dose of atenolol should be employed, in patients with a GFR between 10 and 30 ml/min the dose should be reduced by half, and in patients with a GFR <10 ml/min a reduction by three quarters of the normal dose is recommended.     

Action of the competitive angiotensin II antagonist saralasin during the initial phase of glycerol-induced acute renal failure of the rat

Summary The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml ·kg^–1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure.In healthy rats saralasin (6 g·kg^–1·min^–1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng·kg^–1·min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.Supported by Deutsche Forschungsgemeinschaft     

Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil,a new potent vasodilator

Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( ) was 13.4±8.5 min and elimination half-life ( ) was 2.13±0.49 h. The apparent volume of distribution (Vd) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.     

Constant K+/Na+ excretion ratio during peak diuresis after piretanide but insignificant K+ loss during 24 hours

Summary The effect of piretanide on Na⁺ and K⁺ excretion and on renal haemodynamics has been studied in 14 subjects with a GFR (Inulin clearance) ranging from 140 to 2 ml · min^–1.After a two day fluid and salt balance control period, oral piretanide 6 mg induced a natriuresis and kaliuresis, which was proportional to the GFR of the patients. The ratio of drug-induced K⁺ to Na⁺ excretion was always 0.13, independent of individual GFR. This was only true for the duration of the action of piretanide,, which was 6 h in subjects with normal GFR and 5 h in patients with impaired kidney function. Surprisingly, after, i. e. for 24 h after drug administration, less potassium was lost than in the pretreatment period. Neither the GFR nor the renal blood flow (PAH clearance) of the patients were affected by piretanide.In conclusion, piretanide given once a day was an effective natriuresic agent, even in end-stage renal disease, and it produced relatively little K⁺-loss when given once daily.     

Elimination of azlocillin in patients with biliary t-tube drainage

Summary The pharmacokinetic of azlocillin was followed in five elderly patients after biliary surgery. Total clearance was 138.6±17.7 ml/min when 2.0 g was given as an i.v. bolus injection. The half-life of the -phase averaged 110 min. The total clearance and the half-life of azlocillin were influenced by slight impairment of renal function (creatinine clearance 59.4±13.6 ml/min). In patients with normal liver function biliary excretion of the drug amounted to 5.3±2.8% of the dose (n=3) and the kinetics of biliary excretion were linear. In contrast, in two patients with impaired liver function biliary excretion was 0.2% and 0.5% of the dose, and kinetic analysis of biliary excretion rates revealed at least one zero order step in the excretion process. Renal excretion of the drug amounted to 45.0±17.7% of the dose, which means that 50% of the total clearance of azlocillin has to be accounted for by metabolic clearance.     

Stereoselective analysis of the disposition of tosufloxacin enantiomers in man

Summary The pharmacokinetics of tosufloxacin enantiomers after oral administration of racemic tosufloxacin were examined in healthy volunteers. Only small differences were observed in time to peak concentration (2.6±0.3 [mean ± SEM] h for (+)-tosufloxacin vs 2.4±0.2 h for (–)-tosufloxacin), elimination half-life (3.61±0.24 h vs 3.49±0.23 h), and area under the curve (2.78±0.19 h·g/ml vs 2.87±0.19 h·g/ml); however, peak concentration (0.40±0.03 g/ml vs 0.44±0.03 g/ml), renal clearance (226±10 ml/min vs 202±10 ml/min), and urinary recovery (35.4±2.2% vs 32.4±1.9%) differed significantly between enantiomers.     

Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites

Summary Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0–51 ml · min^–1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21±2.33 (SD) h whilst that in renal failure was 10.15±1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6±10.9 ml·kg^–1h^–1 which was significantly larger than in renal failure where it was 48.8±10.9 ml·kg^–1h^–1. V_d , V_{d ss} and V_c were not significantly different between the two groups. A linear relationship exists between , the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t_1/2 in normal patients was 8.33±2.0 h, whilst in the renal failure group it was 13.37±4.23 h. Total alkylating activity as measured by the nitrobenzylpyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.     

Stereoselective Disposition of Ibuprofen Enantiomers in the Isolated Perfused Rat Kidney

The renal clearance of ibuprofen enantiomer was studied separately in the isolated perfused rat kidney at initial perfusate concentrations of 10 µg/ml (n = 4) and 100 µg/ml (n = 4). Perfusate and urine samples were measured for R(–) and S( + )-ibuprofen using a stereospecific HPLC assay; urine samples were also analyzed after alkaline hydrolysis. Functional viability of the kidney was assured by determining the fractional excretion of glucose and glomerular filtration rate (GFR) at similar perfusion pressures. The clearance of ibuprofen was equivalent to the apparent formation clearance of conjugated enantiomer since unchanged ibuprofen could not be detected in the urine. At 10 and 100 µg/ml, the clearance (±SD) of R(–)-ibuprofen was 2.50 ± 1.28 and 2.19 ± 1.42 µl/min, respectively. At 100 µg/ml, the clearance of S( + )-ibuprofen was 0.805 ± 0.290 µl/min. The protein binding of ibuprofen was found to be concentration dependent and favored the R(–)-enantiomer. The excretion ratio (clearance corrected for free fraction and GFR) of R(–)-ibuprofen was 0.398 ± 0.209 and 0.295 ± 0.209 for perfusate concentrations of 10 and 100 µg/ml, respectively. The excretion ratio of S( + )-ibuprofen was 0.0886 ± 0.0335 for perfusate concentrations of 100 µg/ml. These results demonstrate that the sum of renal mechanisms involved for the clearance of R(–)- and S( + )-ibuprofen was net reabsorption. Ibuprofen was recovered in the urine solely as conjugated material and no evidence of R(–) to S( + ) conversion was observed. In addition, the data suggest that R(–)-ibuprofen is cleared through the kidney faster than its S( + )-enantiomer.     

Enalapril dosage in progressive chronic nephropathy: a randomised, controlled trial

Objective In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken.Methods Forty patients with a median glomerular filtration rate (GFR) of 17 (6–35) ml/min/1.73 m² were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of ⁵¹ Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot.Results In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8–371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5–74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5–30 mg) and 1.88 mg (1.25–5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean±SE decline in renal function was 6.1±1.5 ml/min/1.73 m² per year and in the low-concentration group it was 4.3±14.4 ml/min/1.73 m² per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).Conclusion In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.