Erling K. Brodwall

Kidney Transport in Man of Sulfamethoxazole and Trimethoprim

Evidence is presented to show that trimethoprim (TMP) is subjected to passive, nonionic tubular diffusion in the kidneys. With urinary pH values below 6.2 there is generally net tubular secretion, whe

Pharmacokinetics of sulphadiazine, sulphamethoxazole and trimethoprim in patients with varying renal function

SummaryThe pharmacokinetics of tablets containing combinations of sulphadiazine (SDZ) and trimethoprim (TMP) (co-trimazine) and tablets with sulphamethoxazole (SMZ) and TMP (co-trimoxazole) were compared in patients with different renal functions. In normal renal function, SMZ is more similar to TMP than in renal impairment. In renal impairment although the serum half-life (t1/2) of both active and total SDZ remains similar to that of TMP, the t1/2 of total SMZ becomes several times higher than the t1/2 of TMP. The unchanged SMZ maintains approximately the same elimination velocity in reduced as in normal renal function. Consequently, for co-trimoxazole there is a buildup of SMZ metabolites which can only contribute to toxicity for co-trimoxazole, whereas the co-trimazine components have t1/2 values of the same order, also in renal dysfunction. The distribution volumes of SDZ, SMZ or TMP are the same regardless of renal function. However, the distribution volume of SDZ is closer to that of TMP, i. e. higher than the SMZ values. More active SDZ is excreted in the urine than SMZ both in normal and in reduced renal function. Thus co-trimazine, in addition to having some advantages in the normal individual, is in many respects distinctly more suitable in patients with renal functional impairment. On the basis of the pharmacokinetic properties, dosage schedules are suggested that will give approximately the same plasma levels regardless of renal function.ZusammenfassungDie Pharmakokinetik von Tabletten mit einer Kombination von Sulphadiazin (SDZ) und Trimethoprim (TMP-Co-trimazin) und von Tabletten mit Sulphamethoxazol (SMZ) und TMP (Co-trimoxazol) wurde bei Patienten mit unterschiedlicher Nierenfunktion verglichen. Bei normaler Nierenfunktion gleicht die Pharmakokinetik von SMZ mehr der von TMP als bei Nierenfunktionsstörungen. Obwohl die Serumhalbwertzeit (t1/2) sowohl von aktivem wie vom Gesamt-SDZ derjenigen von TMP ähnlich bleibt, wird der t1/2 Wert des SMZ bei Nierenfunktionsstörungen um ein Mehrfaches höher als der von TMP. Das unveränderte SMZ behält annähernd dieselbe Eliminationsgeschwindigkeit bei eingeschränkter wie bei normaler Nierenfunktion. Folglich sammeln sich bei Co-trimoxazol SMZ Metaboliten an, die nur zur Toxizität von Co-trimoxazol beitragen können, während die Co-trimazin Komponenten bei Nierenfunktionsstörungen t1/2 Werte im gleichen Bereich behalten. Die Verteilungsvolumina von SDZ, SMZ oder TMP sind dieselben, unabhängig von der Nierenfunktion. Jedoch liegt das Verteilungsvolumen von SDZ näher bei dem, von TMP, das heißt, es ist größer als das von SMZ. Sowohl bei normaler als auch bei eingeschränkter Nierenfunktion wird mehr aktives SDZ als SMZ ausgeschieden. In vieler Hinsicht ist Co-trimazin neben seinen Vorteilen beim normalen Patienten eindeutig besser für Patienten mit Nierenfunktionsstörungen. Auf der Basis der pharmakokinetischen Eigenschaften werden Dosierungen vorgeschlagen, die unabhängig von der Nierenfunktion annähernd dieselben Plasmaspiegel erzielen.

Pharmacokinetics of a New Cephalosporin, Cefotaxime (HR 756) in Patients with Different Renal Functions

The pharmacokinetics of intramuscular doses of 1.0 g cefotaxime (HR 759) was studied in 19 persons with normal or reduced renal function. Quantitation was done by both microbiological and high pressure liquid chromatography (HPLC) methods. The HPLC determined unchanged cefotaxime and desacetyl cefotaxime and up to 2 more metabolites in serum, whether unchanged or biotransformed. Patients with renal functions within the normal range (inulin clearance above 100 ml/min) had a mean serum peak concentration of 24.5 ± 10.5 μg/ml. In renal failure, both serum concentrations and the terminal serum half-life (t½β) increased. The mean terminal serum half-life was 2.1 h according to the microbiological assay and 1.5 h according to the HPLC procedure at a glomerular filtration rate (GFR) of 100 ml/min. At an inulin clearance of 10 ml/min, the serum half-life was 6.0 h for the total microbiologically assayed activity and 3.6 h for unchanged drug. There is a linear relationship between log serum half-life of the three moieties of unchanged cefotaxime, total antimicrobial activity (agar diffusion assay with Escherichia coli as indicator), and the major metabolite desacetyl cefotaxime and log clearance of both inulin (ClI) and p-amino-hippuric acid (CIPAH) down to CII, of 10 ml/min. The excretion of unchanged drug in urine during 24 h was reduced gradually upon reduction in renal function from a mean of 59.4 ± 10.2% (range 52.1–77.1) in 5 subjects with GFR above 100 ml/min. The area volume of distribution, e.g. the area of the one-compartment linear open model or during the β-phase of the two-compartment model, Vd,area, was 34.3 ± 10.4 litres according to the microbiological assay and 27.3 ± 13.4 litres for unchanged cefotaxime in patients with renal function within the normal range. The patients with reduced renal function had only insignificantly different distribution volumes. The volumes in normal individuals correspond to 53% of the body weight. The deasacetyl cefotaxime metabolite is excreted more slowly than the parent compound and elimination is relatively longer compared to the parent compound in patients with reduced renal functions. Doses for patients with reduced renal function are discussed. Because nonrenal mechanisms of elimination assume importance when the renal route becomes inefficient, elimination is only moderately prolonged, even in patients with severe renal impairment. Therefore, only moderate reduction in dosage seems necessary.

Relationship between pharmacokinetics and bioavailability of cefroxadine (CGP 9000) and renal function.

The pharmacokinetics and bioavailability of cefroxadine were studied in 15 patients with different renal functions after administration of 0.5 g as oral capsules and as intravenous infusions. Microbiological assays by agar diffusion and high-pressure liquid chromatography may both be used for this agent since no metabolite can be found. The bioavailability is near 100% of the oral dose regardless of renal function. Urinary recovery varied from about 50% in renal glomerular filtration rates (GFR) of less than 7 ml/min to nearly 100% in normal renal function. The serum concentrations, serum elimination half-life and total body clearance were significantly influenced by reduced renal function. Nonrenal elimination occurred in reduced renal function; the maximum serum elimination half-life was 24.6 h. Dose modifications according to renal function are suggested with from three doses/24 in normal renal function to one dose/24 h in patients with GFR of 10 ml/min. The relative distribution volume corresponded to approximately 30% of the body weight. Tubular secretion of cefroxadine took place. The concentrations in urine remained above 32 mg/l for 12 h in all subjects regardless of renal function.