Pharmacokinetics,acetylation-deacetylation,renal clearance,and protein binding of sulphamerazine,N4-acetylsulphamerazine,and N4-trideuteroacetylsulphamerazine in ‘fast’ and ‘slow’ acetylators

Sulphamerazine shows a clear acetylator phenotype. The half-life of elimination of sulphamerazine is 12 h in ‘fast’ and 24 h in ‘slow’ acetylators. N₄-Acetylsulphamerazine is eliminated biphasically, characterized by half-lives of 5 and 12 h in ‘fast’ and 5 and 24 h in ‘slow’ acetylators. Protein binding of sulphamerazine (86 per cent) and N₄-acetylsulphamerazine (92 per cent) is independent of acetylator phenotype or the origin of the compound, whether it is present in the body as parent compound or metabolite. The renal clearance of sulphamerazine (20ml min ⁻¹) and N₄-acetylsulphamerazine (300–500 ml min⁻¹) is independent of the acetylator type and the origin of the compound. The existence of an acetylation-deacetylation equilibrium in the metabolism of sulphamerazine has been demonstrated with the test drug N₄-trideuteroacetylsulpha- merazine, which inhibits the renal excretion and clearance of N₄-acetylsulphamerazine.     

Pharmacokinetics and mechanism of renal excretion of short acting sulphonamides and N4-acetylsulphonamide derivatives in man

Summary The pharmacokinetics of short acting sulphonamides and a series of N₄-acetylsulphonamide derivatives has been investigated. Sulphonamides with a sulphur atom two atomic bond distances from the N₁ atom are excreted by active tubular secretion, e.g. sulphamethizole, sulphaethidole and sulphathiazole. When the sulphur atom is replaced by an oxygen or nitrogen atom, active renal excretion no longer occurs. N₄-acetylsulphonamides are excreted by active tubular secretion. The renal clearance values of the N₄-acetylsulphonamides are not influenced by the substituent at the N₁ position. Two groups of N₄-acetylsulphonamides can be distinguished. One has a T_1/2 of 4–6 h and a renal clearance value of 20–60 ml/min and the second has a T_1/2 of 10–20 h and a renal clearance of less than 10 ml/min. N₄-acetylsulphonamides are deacetylated to the extent of about 5%.     

Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance

Aims N -Desmethylclozapine and clozapine N -oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.
Methods From 15  psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2  h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.
Results The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N -desmethylclozapine 9.7%, and clozapine N -oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N -desmethylclozapine and clozapine N -oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N -desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.
Conclusions Clozapine, N -desmethylclozapine and clozapine N -oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N -demethylation and N -oxidation must make major contributions to the total fate of clozapine in patients.     

Skeletal muscle binding and renal excretion of digoxin in man

Summary Ten healthy subjects were treated with three or four different doses of digoxin, 0.25 to 0.88 mg daily, in random order. Digoxin concentrations in serum (SDC) and skeletal muscle (SMDC) were determined as well as its renal clearance after 2 weeks of treatment with each dose. The mean ratio SMDC/SDC decreased non-significantly by about 20% from 33±15 at the lowest SDC interval (0.5–0.9 nmol/l) to 28±7 at the highest concentration interval (2.0–2.4 nmol/l). This is in accordance with findings from previous studies. No significant change was observed in the renal clearance of digoxin with increasing digoxin concentration, supporting the concept of first-order renal elimination of digoxin.     

Pharmacokinetics: metabolism and renal excretion of quinolones in man

The quinolones are relatively poorly absorbed from the gastrointestinal tract. The elimination proceeds mainly by renal excretion. The half-life of elimination depends on the molecular structure and varies between 2 and 10 h. Impaired kidney function is expected to increase the half-life of elimination. though this effect is not always observed. Since the 4-oxo-metabolites show a higher renal clearance than the parent drug, renal impairment will result in a cumulation of the metabolites in the body.     

Pharmacokinetics, N1-glucuronidation and N4-acetylation of sulfadimethoxine in man

Sulfadimethoxine is metabolized byO-dealkylation, N4-acetylation and N1-glucuronidation. In man, only N1-glucuronidation and N4-acetylation takes place, leading to the final double conjugate N4-acetylsulfadimethoxine-N1-glucuronide. The N1-glucuronides are directly measured by high pressure liquid chromatography. When N4-acetylsulfadimethoxine is administered as parent drug, 30% of the dose is N1-glucuronidated and excreted. Fast acetylators show a shorter half-life for sulfadimethoxine than slow acetylators (27.8±4.2 h versus 36.3±5.4 h; P=0.013), similarly the half-life of the N4-acetyl conjugate is also shorter in fast acetylators (41.3±5.2 h versus 53.5±8.5 h, P=0.036). No measurable plasma concentrations of the N1-glucuronides from sulfadimethoxine are found in plasma. N1-glucuronidation results in a 75% decrease in protein binding of sulfadimethoxine. N4-acetylsulfadimethoxine and its N1-glucuronide showed the same high protein binding of 99%. Approximately 50–60% of the oral dose of sulfadimethoxine is excreted in the urine, leaving 40–50% for excretion into bile and faeces.     

Pharmacokinetics and acetylation of sulfa-2-monomethoxine in humans.

In humans sulfa-2-monomethoxine (S) is metabolized by N4-acetylation (39.9 +/- 8.0 per cent). After an oral dose, S is eliminated biphasically (t1/2, 5.2 +/- 1.6 h and 13.2 +/- 3.4 h) which is similar in both fast and slow acetylators. The metabolite N4-acetylsulfa-2-monomethoxine (N4) is eliminated monophasically (t1/2, 30.0 +/- 5.7 h). The intrinsic mean residence time (MRT) of N4 is 33.5 +/- 8.8 h. The mean total body clearance of S is 11.6 +/- 2.7 ml min-1, and the Vdss is 12.3 +/- 1.01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min-1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min-1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41.0 +/- 6.2 per cent) and as N4 acetyl conjugate (39.9 +/- 8.0 per cent).     

Urine flow-dependence of theophylline renal clearance in man

Theophylline renal clearance is highly dependent on urine flow rate and is neither concentration nor dose related. To examine the flow dependency, theophylline was adminstered in single doses (4.3 mg/kg to 8.6 mg/kg) to 14 volunteers. Seven of these volunteers participated in studies in which theophylline and metabolite concentrations were held constant at six different levels. Due to the diuretic effect of theophylline, its renal clearance contributed up to 70% of the time-averaged total clearance, dose/total area, in the first hour after a single dose. The contribution then dropped to 5% of the time-averaged total clearance when the normal urine flow rate was restored. As a consequence of extensive tubular reabsorption, the urine/plasma concentration ratio of theophylline varied with urine flow rate and approached the value of the unbound fraction in plasma. On assumption that the reabsorption is passive, a mathematical model was used to explain the urine flow dependence of reabsorption and, therefore, the renal clearance of theophylline.This work was supported in part by Grant GM 26691 from the National Institute of General Medical Sciences.Sidney Riegelman, Ph.D., died on April 4, 1981.     

Pharmacokinetics, metabolism, and renal excretion of sulfadimidine and its N4-acetyl and hydroxy metabolites in humans

Sulfadimidine is acetylated and hydroxylated in humans. The hydroxylation pathways account for 10-20% of the dose, leaving the acetylation as the major metabolic pathway. The hydroxylation pathways are independent of the acetylator phenotype. The plasma concentration-time curve of sulfadimidine in fast acetylators is biphasic, with half-lives of 1.7 and 5.4 h, whereas that in slow acetylators is monophasic, with a half-life of 7.6 h. Hydroxylation of a methyl group in sulfadimidine lowers the protein binding from 90 to 60%, while acetylation does not affect the protein binding. Methyl hydroxylation markedly increases the renal clearance.     

Delayed elimination of triamterene and its active metabolite in chronic renal failure

Summary The kinetics of triamterene and its active phase II metabolite were studied in 32 patients with various degrees of impaired renal function; the creatinine clearances ranged from 135 to 10 ml/min. The area under the plasma concentration-time curves (AUC) for triamterene were not influenced by kidney function, but the AUCs for the effective metabolite OH-TA-ester were significantly elevated in renal failure, indicating accumulation of the metabolite. Urinary recovery of triamterene and its metabolite over a 48 h collection period was significantly reduced in renal failure. This is considered to be due to delayed urinary excretion, corresponding to reduced renal clearance. The renal clearance of the native drug exceeded that of the metabolite, because of their different protein binding, 55% for triamterene and 91% for the metabolite. The latter is eliminated almost exclusively via tubular secretion and extrarenal elimination is less important. Administration of this antikaliuretic is therefore considered hazardous in patients with impaired kidney function.     

Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol

AIMS: Previous studies suggest that estimated creatinine clearance, the conventional measure of renal function, does not adequately reflect changes in renal drug handling in some patients, including the immunosuppressed. The aim of this study was to develop and validate a cocktail of markers, to be given in a single administration, capable of detecting alterations in the renal elimination pathways of glomerular filtration, tubular secretion and tubular reabsorption. METHODS: Healthy male subjects (n = 12) received intravenously infused 2500 mg sinistrin (glomerular filtration) and 440 mg p-aminohippuric acid (PAH; anion secretion), and orally administered 100 mg fluconazole (reabsorption) and 15 mg rac-pindolol (cation secretion). The potential interaction between these markers was investigated in a pharmacokinetic study where markers (M) or fluconazole (F) were administered alone or together (M + F). Validated analytical methods were used to measure plasma and urine concentrations in order to quantify the renal handling of each marker. Plasma protein binding of fluconazole was measured by ultrafiltration. All subjects had an estimated creatinine clearance within the normal range. The renal clearance of each marker (mean+/- s.d.) was calculated as the ratio of the amount excreted in urine and the area-under-the-concentration-time curve. Statistical comparisons were made using a paired t-test and 95% confidence intervals were reported. RESULTS: The renal clearances of sinistrin (M: 119 +/- 31 ml min(-1); M + F: 130 +/- 40 ml min(-1); P = 0.32), PAH (M: 469 +/- 145 ml min(-1); M + F: 467 +/- 146 ml min(-1); P = 0.95), R-pindolol (M: 204 +/- 41 ml min(-1); M + F: 190 +/- 41 ml min(-1); P = 0.39; n = 11), S-pindolol (M: 225 +/- 55 ml min(-1); M + F: 209 +/- 60 ml min(-1); P = 0.27; n = 11) and fluconazole (F: 14.9 +/- 3.8 ml min(-1); M + F: 13.6 +/- 3.4 ml min(-1); P = 0.16) were similar when the markers or fluconazole were administered alone (M or F) or as a cocktail (M + F). CONCLUSIONS: This study found no interaction between markers and fluconazole in healthy male subjects, suggesting that a single administration of this cocktail of markers of different renal processes can be used to simultaneously investigate pathways of renal drug elimination.     

Effect of pinacidil on renal haemodynamics,tubular function and plasma levels of angiotensin II,aldosterone and atrial natriuretic peptide in healthy man

Summary The effects of pinacidil on renal haemodynamics, tubular function evaluated by the lithium clearance technique and the plasma levels of angiotensin II (Ang II), aldosterone (Aldo) and atrial natriuretic peptide (ANP) have been evaluated in 12 healthy volunteers given pinacidil 0.1 mg/kg IV in comparison with a placebo given to 13 different healthy volunteers.Pinacidil induced significant reductions in glomerular filtration rate (–5%), renal plasma flow (–12%), urine output (–35%), urinary sodium excretion (–20%), and the fractional excretion of sodium (–17%) and potassium (–29%). Lithium clearance and proximal and distal absolute and fractional reabsorption of sodium were not significantly changed. Ang II and Aldo were significantly increased (80% and 115%, respectively) and ANP was unchanged. The mean arterial blood pressure was not significantly changed by pinacidil, but the heart rate was increased (22%).It is concluded that bolus IV injection of pinacidil in healthy subjects reduced renal blood flow, urine volume and the urinary excretion of sodium and potassium, whereas segmental tubular function was unchanged. The increase in heart rate and activation of the renin-agiotensin-aldosterone system are most likely to be secondary to stimulation of the sympathetic nervous system caused by the vasodilator effect of pinacidil.     

Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption

The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one‐compartment model. Considerable interindividual variability was observed in the oral clearance (CL/F) and the apparent volume of distribution (V/F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral‐to‐apical direction in P‐glycoprotein‐expressing renal epithelial LLC‐GA5‐COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P‐glycoprotein in the renal tubule and is taken up by the postulated H⁺/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug‐metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance (CL) and/or the bioavailability (F) of flecainide. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetics of bendazac-lysine and 5-hydroxybendazac in patients with renal insufficiency

Summary The pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, have been investigated in 15 patients with moderate to severe renal insufficiency and renal failure following a single oral dose of 500 mg bendazac-lysine. The pharmacokinetic parameters were compared to those obtained in 10 healthy adult volunteers.The rate and the extent of absorption of bendazac was not modified in the patients with moderate and severe renal insufficiency, nor was there any change in plasma t_max, C_max, apparent elimination t_1/2 and AUC.There was a significant increase in the unbound fraction of bendazac in renal failure patients undergoing haemodialysis, with a consequent increase in the apparent volume of distribution (V/F) and apparent plasma clearance (CL/F), and a decrease in plasma C_max and AUC. Simultaneous changes of V/F and CL/F lead to an unchanged plasma t_1/2 in these patients. Renal clearance (CL_R) was decreased, but CL/F was not affected, since renal excretion is a minor route of elimination of bendazac.Bendazac is mostly eliminated by metabolism to 5-hydroxybendazac, in healthy subjects >60% of a dose being excreted in urine as 5-hydroxybendazac and its glucuronide. In patients with renal insufficiency urinary excretion of 5-hydroxybendazac was decreased and the systemic availability of the metabolite (AUC), was increased about three-fold, irrespective of the degree of renal failure. Plasma 5-hydroxybendazac glucuronide accumulated according to the degree of renal insufficiency.Overall it can be assumed that the pharmacological effect of the drug will not be enhanced in renal failure and that the dosage regimen of bendazac-lysine in such patients need not be modified.     

Influence of acute renal failure on the protein binding of drugs in animals and in man

Summary Serum protein binding of phenylbutazone has been measured in the rat, guinea pig, cat, rabbit and dog, and the influence on it of renal failure induced by uranyl nitrate injection has been studied. In all species a clearcut decrease in binding was observed after the occurrence of renal failure; the time course of the fall in binding correlated well with development of renal failure. In further experiments, serum protein binding of two acidic drugs (phenylbutazone, warfarin), two basic drugs (papaverine, quinidine) and one neutral drug (digitoxin) was studied in rabbits with experimental renal failure, and the results compared with those obtained in patients with acute renal failure. In the rabbits, a decrease in the binding of phenylbutazone, warfarin, papaverine and quinidine was found, whereas protein binding of digitoxin was unchanged. In man, there was a definite fall in protein binding of phenylbutazone and digitoxin, a small decrease for warfarin and papaverine, and a slight increase for quinidine.     

Quantitation of hepatic and pulmonary first-pass effect and its implications in pharmacokinetic study. I. Pharmacokinetics of chloroform in man

Theoretical equations are derived to estimate the extent of the hepatic and pulmonary first-pass effect after oral and intraperitoneal administration. This first-pass effect is taken into consideration for the determination of apparent volume of distribution and body clearance. Calculations using data for two normal adult subjects taken from the literature suggest that the fractions of chloroform metabolized in the liver and excreted intact from the lung in the first pass are maximally 0.38 and 0.172. respectively. The apparent volumes of distribution of chloroform in these two subjects are 238 and 283% of their body weight in terms of blood concentration. Close agreement between the predicted and experimental values for the pulmonary excretion clearance is also found.     

N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯及其代谢产物在大鼠离体肝脏中的代谢动力学

利用大鼠肝脏灌流技术研究了N,N-二甲氨基甲酸5-(1,3,3-三甲基吲哚满)酯(TMDMC)及其代谢产物在大鼠离体肝脏中的代谢动力学,TMDMC在改良的灌流液中作循环式灌流,于不同时间留取少量灌流液,用高效液相色谱(HPLC)作药物的定量分析,结果显示其在离体灌流肝脏中的清除模型符合两相消除模型,动力学参数表明,TMDMC在肝内的分布较快,其分布半衰期仅为4min,肝脏分布容积为102.4 ml,清除率是0.67ml·min~(-1),清除比率为0.027.灌流2h时,其浓度已下降了73％.与此同时,TMDMC的代谢产物逐渐生成,其中以产物Ⅲ的生成量最大,其最高生成浓度(C_(max))为447.1 μg·ml~(-1),2 h产物Ⅲ的生成总量已达TMDMC灌流量的25.6％.而代谢产物Ⅱ,Ⅵ的生成较少,其C_(max)分别是20.4μg·ml~(-1)和20.7μg·ml~(-1).     

Pharmacokinetics of tryptophan,renal handling of kynurenine and the effect of nicotinamide on its appearance in plasma and urine following L-tryptophan loading of healthy subjects

Summary The pharmacokinetics of tryptophan, the temporal occurence of kynurenine (KYN) and 3-hydroxykynurenine (3-HK) in plasma and urine, and the effect of nicotinamide on tryptophan metabolism were studied in 6 healthy subjects after oral administration of L-tryptophan 100 mg per kg body weight. The peak concentration of tryptophan in plasma occurred after 1 to 2 h, tryptophan disappeared linearly from 2 to 5 h and exponentially from 5 to 8 h. Urinary tryptophan excretion was negligible. The peak concentration of KYN in plasma occurred after 4 h and it was correlated significantly with the area under the plasma curve (AUC) of KYN of the subjects investigated. The AUC in plasma of KYN was significantly correlated with urinary KYN excretion within individuals, but not in the group as a whole. The data suggest that KYN was reabsorbed by renal tubules and that the degree of reabsorption was subject to large interindividual variation. The peak concentration in plasma of 3-HK occurred 11 min later than that of KYN. The results suggest that the net tubular effect on 3-HK was secretion. Pre-treatment with nicotinamide (0.5 g three times daily) resulted in considerable decreases in AUC in plasma, and in urinary excretion of KYN and 3-HK, indicating inhibition of liver tryptophan pyrrolase. The concomitant increase in AUC in plasma of free and total tryptophan was insignificant.As only a relatively small amount of tryptophan is catabolized by tryptophan pyrrolase following an L-tryptophan load, cautious interpretation is recommended of urinary KYN excretion as an indicator of tryptophan break down in investigation of different subjects.Preliminary results from the nicotinamide study were presented at the 3rd meeting of the International Study Group for Tryptophan Research, Kyoto, Japan, 4–7th August 1980