Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency.

Verbeeck, Roger K.; Tjandramaga, T. B.; Mullie, A.; Verbesselt, René; Verberckmoes, René; Schepper, P. De

doi:10.1111/j.1365-2125.1979.tb00932.x

Cited by 75 publications

(19 citation statements)

References 17 publications

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“…Other niechanisms responsible for the decline in CLNR of carumonam have not been elucidated. A similar decline in the nonrenal (mainly hepatic) cleararlce of other drugs has previously been reported in patients with renal failure (5,7,8,19). That certain!…”

Section: Methodsmentioning

confidence: 51%

Pharmacokinetics of carumonam in patients with renal insufficiency

Horber¹,

Egger²,

Weidekamm³

et al. 1986

Antimicrob Agents Chemother

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The pharmacokinetics of carumonam after a single 1,000-mg intravenous infusion (20 min) were evaluated in four groups of subjects who had various degrees of renal impairment: group 1, CLCR > 60 ml/min; group 2, CLCR = 30 to 60 ml/min; group 3, CLCR = 10 to 30 ml/min; and group 4, CLCR < 10 ml/min). The elimination half-life of carumonam increased with decreasing creatinine clearance (CLCR) from 1.7 h in group 1 to 11.3 h in group 4. Peak carumonam concentration (103 ,ug/ml) and steady-state volume of distribution (12.8 liters) did not change with decreasing CLCR. Total body clearance (r = 0.98), renal clearance (r = 0.98), and nonrenal clearance (r = 0.67) of carumonam correlated with decreasing CLCR. Mean nonrenal clearance was 21 ml/min in group 1 and 12 ml/min in group 4. With regard to dosage, patients with a CLCR above 60 ml/min should receive their standard maintenance dose of carumonam without any changes; patients with a CLCR between 30 and 60 ml/min should receive the dose every 12 h; and individuals with a CLCR between 10 and 30 ml/min should be given the dose once a day. Patients with a CLCR of less than 10 ml/min should receive one-half of the dose once a day. Our recommended dosage regimens should produce within the CLCR borderlines of each group average plasma concentrations that are between one and two times that achieved in normal subjects with a t.i.d. dosage regimen.Carumonam (Fig. 1) is a new synthetic N-sulfonated monocyclic beta-lactam antibiotic. This compound is highly stable against both chromosomal-and plasmid-mediated beta-lactamases and has broad-spectrum activities against gram-negative bacteria. The in vivo and in vitro activities of carumonam are comparable to those of aztreonam, a structurally related compound (9). The pharmacokinetic characteristics of carumonam include low protein binding (Junbound = 0.82); elimination primarily by glomerular filtration (furine = 0.7 to 0.9); distribution into extracellular water space; and a half-life of elimination (t01/2) between 1.4 and 2.3 h (20).These pharmacokinetic characteristics are similar to those of the cephalosporins cefsulodin, ceftizoxime, and ceftazidime (15). As with these and other beta-lactam antibiotics with low protein binding and high urinary recovery, loss of renal function should result in an almost proportional decrease in body clearance and a corresponding increase in biological half-life for carumonam.The purpose of this study was to define the pharmacokinetic behavior of carumonam in patients with renal insufficiency and to deduce from these data appropriate dosage schedules for such patients.

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Section: Methodsmentioning

confidence: 51%

Pharmacokinetics of carumonam in patients with renal insufficiency

Horber¹,

Egger²,

Weidekamm³

et al. 1986

Antimicrob Agents Chemother

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“…The mechanism(s) responsible for this decline in CLNR has not been elucidated for f-lactam antibiotics that are primarily eliminated unchanged. Decreases in hepatic clearance due to decreases in drugmetabolizing enzyme activities in acute or chronic renal failure patients are, on the other hand, well known (4,7,18).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency

Kneer

Tam

Blouin

et al. 1989

Antimicrob Agents Chemother

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The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLs), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t112^) was prolonged from 2.46 ± 0.33 h in normal subjects to 29.1 13.9 h in patients with CLCR of <10 ml/min per 1.73 i2. Correspondingly, CLs and CLR decreased from 1.77 0.27 and 1.42 0.25 mI/mi per kg to 0.14 + 0.04 and 0.04 + 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P > 0.05). After oral administration, the elimination parameters, tl/2,, and CLR, were insignificantly different from the intravenous data (P > 0.05).Furthermore, the bioavailability (F) of cefetamet pivoxil (45 13%) was not altered by renal failure (P > 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 0.74 versus 14.8 6.14 ,ug/ml and 3.9 ± 1.1 versus 8.4 1.7 h, respectively; P < 0.05).Based on these observations, it is recommended that patients with CLCR of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily.Patients with CLCR between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLCR of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.Cefetamet pivoxil is the prodrug (pivaloyloxymethylester) of a new broad-spectrum cephalosporin antibiotic, cefetamet. This compound possesses a broad spectrum of antimicrobial activity against many aerobic gram-positive and gram-negative organisms (19). Previous pharmacokinetic studies in normal healthy volunteers revealed that the lowprotein-bound (22%) cefetamet is mainly eliminated by the kidneys via glomerular filtration (2, 12). This kinetic behavior is similar to that of other P-lactam antibiotics with low protein binding and high urinary recovery (e.g., carumonam [11], ceftizoxime [1,15], and ceftazidime [1,15]). Consequently, the pharmacokinetics of cefetamet are expected to be dependent on changes in renal function.The objectives of this study were to determine the pharmacokinetics of cefetamet and cefetamet pivoxil after intravenous and oral administration to patients with various degrees of impaired renal function, to compare these results with those obtained from healthy volunteers who have normal renal functions, and to determine dosage guidelines for patients with renal impairment. MATERIALS AND METHODSSubjects. Nine healthy volunteers (7 men and 2 women) and 38 patients (22 men and ...

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“…In a recent study on disposition kinetics of the new salicylate analgesic diflusinal Merck,Sharp & Dohme Research Laboratories) in patients with varying degrees of renal function impairment, we observed clearly lower plasma drug concentrations in patients with end-stage renal failure receiving maintenance aluminum hydroxide therapy (Verbeeck, Tjandramaga, Mullie, Verbesselt, Verberckmoes & De Schepper, 1979). To examine the possibility of reduced bioavailability of diflunisal due to the concomitant administration of aluminum hydroxide in this patient group, the effect of aluminum hydroxide co-administration on the extent of diflunisal absorption was evaluated in normal subjects.…”

Section: Introductionmentioning

confidence: 99%

Effect of aluminum hydroxide on diflunisal absorption.

Verbeeck¹,

Tjandramaga²,

Mullie³

et al. 1979

Brit J Clinical Pharma

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I The effect of aluminum hydroxide on the oral absorption of diflunisal was studied in healthy subjects. 2 Relative bioavailability of the oral diflunisal dose (500 mg) was estimated by comparison of the areas under plasma concentration versus time curves, and comparison of the amount of drug (unchanged + glucuronides) excreted in the urine. 3 From the AUC-method, a relative bioavailability of 0.60 was calculated. A similar value (F =0.63) was obtained from the urinary excretion data. 4 The results indicate that co-administration of aluminum hydroxide reduces the bioavailability of oral diflusinal by about 40%.

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Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency.

Cited by 75 publications

References 17 publications

Pharmacokinetics of carumonam in patients with renal insufficiency

Pharmacokinetics of carumonam in patients with renal insufficiency

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency

Effect of aluminum hydroxide on diflunisal absorption.

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