Simultaneous tubular excretion and reabsorption of pindolol in man

Summary The plasma concentrations of pindolol have been examined following the administration of single doses of 15 mg tablets to eight healthy male subjects. The apparent half-life of elimination in plasma (t_1/2=4.05 h) and in urine (t_1/2=3.21 h) was calculated using conventional pharmacokinetic methods. The renal clearance was estimated by plotting urinary excretion rates versus plasma concentrations; for all subjects these plots were curved. In addition to these graphical estimations, the plasma concentrations of pindolol and the urinary excretion data for each volunteer were simultaneously fitted using a one or two-compartment open body model; a computer program using non-linear regression algorithms was used. This procedure did not give an adequate fit to the data. Another type of data analysis, using a population — based model, permitted us to show that the renal elimination of pindolol in man comprises of two separate processes — tubular secretion and reabsorption, which was partially saturable under the experimental conditions. The theoretical relevance and clinical significance of these findings are discussed.Supported by the Fonds National Suisse de la Recherche Scientifique     

Saturable Processes Affecting Renal Clearance of Cefixime in Dogs

The pharmacokinetics of cefixime, a new orally active cephalosporin, was studied after an intravenous dose of 50 mg/kg to four beagle dogs. Cefixime was shown to exhibit concentration dependent serum protein binding and saturable tubular reabsorption. The drug was excreted mainly in the urine, the net result of glomerular filtration and saturable tubular reabsorption. The experimental results were analyzed by model independent pharmacokinetic equations and with theoretical models describing renal clearance. Modification of the models, based on observed data, was proposed. The experimental methods employed and the pharmacokinetic approach offered in this study can be applied to drugs that exhibit concentration dependent protein binding and saturable renal elimination processes.     

Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers

Summary Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg^–1.The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased.These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range.The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.     

Dose-dependent absorption of amoxicillin in patients with an ileostomy

Summary Amoxicillin was given as single doses of 375, 700, 1500, 3000 and 6000 mg an oral suspension to four volunteers with an ileostomy and with no active intestinal disease after an overnight fast. The excretion of amoxicillin and its penicilloic acid was followed in samples taken from the ileostomy and in urine produced over 6 h. Beta-lactamase activity was measured in ileal fluid and none was found. The percentage of the dose recovered from the ileostomy increased successively from 8% at the lowest dose to 77% at the highest dose. A complementary excretion pattern of amoxicillin was found in the urine, amounting to 70 % recovery at the lowest dose to 23 % at the highest dose. The results confirm the dose-dependence of the absorption of amoxicillin, which could at least in part be due to specialised absorption of this drug in humans.     

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.     

Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption

Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).     

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.     

HPLC法测定头孢羟氨苄及其有关物质含量

目的建立头孢羟氨苄有关物质的HPLC分析方法。方法采用ODS柱(Polaris250mm×4.6mm,5μm),以0.05mol/L磷酸盐缓冲液(用10mol/L氢氧化钾调节pH值为5.5)-乙腈(96∶4)为流动相,流速为0.7ml/min,检测波长为230nm。结果头孢羟氨苄、有关物质α-对羟基苯甘氨酸、7-氨基去乙酰氧基头孢烷酸(7-ADCA)的线性范围分别为0.125～1.0mg/ml(r=0.9997)、0.312～20μg/ml(r=0.9999)、0.312～20μg/ml(r=0.9999)。结论本方法可用于头孢羟氨苄及其有关物质含量的测定,方法准确、灵敏、简便。     

Pharmacokinetics of cefadroxil in patients with terminal renal impairment

The pharmacokinetics of cefadroxil were studied in 15 subjects divided into 3 groups: healthy volunteers, patients with terminal renal impairment in interdialysis sessions and patients with terminal renal impairment undergoing hemodialysis sessions.The serum levels of the antibiotic were determined by a microbiologic plate diffusion method using Bacillus subtilis (ATCC no. 6633) as the test organism.Renal impairment causes a decrease in the elimination rate of the antibiotic. The serum half-life has a value of 1.20 ± 0.21 h in the healthy volunteers, 26.56 ± 8.00h in patients in interdialysis periods and 2.45 ± 0.72 h in patients undergoing hemodialysis sessions.Hemodialysis partially restores absorption and elimination of cefadroxil to levels which approach those established in healthy volunteers.     

Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption

AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.     

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.     

The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3–31.31), plasma clearance (249–288 ml/min), and renal clearance (151–177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54±6, 19±4, 6.5±0.7 and 5.5±0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3±0.4, 2.2 ±0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83±0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 ±226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 ±241). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92–94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0–1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.     

A pharmacokinetic comparison of cephalexin and cefadroxil using HPLC assay procedures

The pharmacokinetics of cephalexin and cefadroxil were compared following single 500 mg oral doses to 12 healthy male volunteers. Doses were administered after an overnight fast according to a crossover design. Plasma and urinary levels of both compounds were determined by HPLC procedures. Cephalexin was absorbed rapidly, achieving a mean peak plasma level of 17.5 micrograms ml-1 at 1 h, compared to 16 micrograms ml-1 at 1.8 h for cefadroxil. Elimination half-lives of cephalexin and cefadroxil were 0.7 and 1.1 h, respectively. The area under the cefadroxil plasma curve was significantly larger than that for cephalexin. However, after allowing for differences in elimination rate constants and assuming equal distribution volumes, plasma data indicated the compounds were equally well absorbed. Only 70 per cent of cefadroxil was recovered in urine compared to 87 per cent of cephalexin during the 12 h following drug administration. The therapeutic significance of the different pharmacokinetic characteristics of cephalexin and cefadroxil, if any, may be a function also of their pharmacologic activity and/or the sensitivity of the target organism.     

Distribution and elimination of hydroflumethiazide in man

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion, HFT behaved according to a three-compartment model. Two distribution phases were observed, with mean half-lives of 0.26 and 0.85 h, reflecting distribution to red blood cells and tissues. Mean biological half-life (t_1/2β ) after infusion was 5.2 h. Renal blood and plasma clearance of HFT, as well as the ratio renal blood clearance/renal plasma clearance of HFT, were lower after infusion than during the infusion, due to the distribution characteristics of HFT. After a single oral dose of 2 μmol/kg, t_1/2β was significantly shorter in all subjects than after a single oral dose of 6 μmol/kg, with mean t_1/2β of 8.7 and 17.9 h, respectively. Due to lack of a sufficiently sensitive method for determination of HFT in plasma, it could not be established whether the observed dose-dependent difference in biological half-life of HFT was caused by variation in renal clearance and/or the volume of distribution.     

Felodipine reduces the absorption of theophylline in man

Summary Ten healthy male volunteers (mean age 26 years) received 200 mg theophylline aminopropanol orally 8-hourly for 4 days, followed by 5 mg felodipine 8-hourly for 6 days, and then the combination of oral felodipine and theophylline for a further 4 days. Plasma concentrations of theophylline and felodipine were determined, and theophylline and its metabolites in urine were also measured.Felodipine led to a reduction in the plasma AUC of theophylline of 18.3%. The metabolic and renal clearances of theophylline remained unchanged, but the total recovery of theophylline-derived products was significantly reduced during felodipine treatment.No change in felodipine pharmacokinetics was observed during simultaneous treatment with theophylline.Compared to theophylline treatment alone, the diastolic blood pressure was significantly reduced during felodipine treatment alone and in combination with theophylline.It is concluded that felodipine slightly but significantly lowered the plasma theophylline concentration by interfering with its absorption. The interaction in most instances would probably be of minor clinical consequence.     

高效毛细管电泳法同时测定血浆中头孢羟氨苄和甲氧苄啶的含量

采用毛细管区带电泳法(CZE)测定血浆中头孢羟氨苄、甲氧苄啶的含量。以20mmol/L硼砂(pH7.1)为背景电解质,35cm×75μm(i.d)未涂层毛细管为色谱柱,于267nm处检测,操作温度25℃,分离电压为20kV,采用峰面积外标法定量。头孢羟氨苄和甲氧苄啶的线性范围分别为0.4~4.0和0.25~4.0μg/ml,检出限分别为0.1和0.18μg/ml(S/N=3)。该方法测得头孢羟氨苄和甲氧苄啶的在低、中、高浓度下的回收率均在95%以上,迁移时间的RSD分别为0.43%、1.44%;峰面积的RSD分别为3.34%、4.0%,日内、日间精密度均符合方法学要求。该方法用量少,简便,快速,准确,适合于血药浓度的监测。     

头孢羟氨苄治疗急性咽炎、扁桃体炎的疗效观察

目的:观察头孢羟氨苄治疗急性咽炎、扁桃体炎的临床疗效。方法:130例急性咽炎、扁桃体炎患儿随机分为治疗组65例,给予头孢羟氨苄30 mg/(kg·d)治疗;对照组65例,给予阿莫西林40 mg/(kg·d)治疗。结果:治疗组与对照组显效率分别为32.3％和16.9％(x2=4.15,P<0.05),总有效率分别为81.5％和55.4％(x2=10.3,P<0.01)。结论:头孢羟氨苄治疗急性咽炎、扁桃体炎有良好疗效。     

克拉霉素与头孢羟氨苄甲氧苄啶治疗慢性鼻窦炎的疗效比较

目的 比较克拉霉素与头孢羟氨苄甲氧苄啶应用于慢性鼻窦炎的临床疗效.方法 选取2010年5月至2012年5月我院收治的慢性鼻窦炎患者86例.随机分为对照组和实验组,每组43例.对照组给予头孢羟氨苄甲氧苄啶治疗,实验组给予克拉霉素治疗.通过症状视觉模拟量表（VAS）、内镜黏膜形态评估（Lund-Kennedy评分法）、Lund-Mackey CT评分情况以及鼻腔黏膜纤毛传输时间,比较两组患者经不同药物治疗后的临床疗效.结果 ①实验组患者在治疗8周、12周和16周后,临床疗效明显优于对照组（P〈0.05）;②实验组患者的VAS评分、Lund-Kennedy评分、Lund-Mackay CT评分均显著低于治疗前和对照组（P〈0.05）;③实验组治疗后黏膜纤毛传输速度提高程度优于对照组（P〈0.05）.结论 克拉霉素治疗慢性鼻窦炎,具有临床疗效显著、安全可靠等优点,值得临床推广和应用.     

Renal digoxin clearance: Dependence on plasma digoxin and diuresis

Summary The renal handling of digoxin in animals involves glomerular filtration, tubular secretion and tubular reabsorption, while only glomerular filtration and tubular secretion have been described in humans. The influence of plasma digoxin and urine flow on the renal handling of digoxin was investigated in 6 healthy volunteers. Non-glomerular renal excretion of digoxin (tubular secretion minus tubular reabsorption) was inversely correlated with plasma digoxin concentration and directly with urine flow. Hence, the present study demonstrated the occurrence of tubular reabsorption in addition to glomerular filtration and tubular secretion of digoxin. The results suggest that renal clearance of digoxin should be increased by increased urine flow, which might be of importance during digoxin toxicity.     

Albendazole kinetics in patients with echinococcosis: Delayed absorption and impaired elimination in cholestasis

Summary The pharmacokinetics of albendazole and its main metabolite, albendazole sulphoxide, have been examined after giving a single oral dose of 200 mg albendazole to 19 patients with either Echinococcus multilocularis or E. granulosus, 5 of whom had significant extrahepatic obstruction due to the underlying disease. The AUC of albendazole sulphoxide was increased in the latter patients (mean 122 mol · h · l^–1 compared to 17 mol · h · l^–1 in the non-obstructed group). Obstructed patients had delayed absorption, k_a averaging 0.39 compared to 1.41 h^–1 in non-obstructed patients. The corresponding elimination rate constant, k_e was also prolonged, averaging 0.041 and 0.13 h^–1 in the two groups, respectively. Four patients were restudied after complete or partial resolution of the cholestasis. The pharmacokinetic parameters in them had returned towards values comparable to those in the non-obstructed patients.