Pharmacokinetics of Minocycline in Renal Failure

The pharmacokinetics of minocycline have been studied after single intravenous infusions and repeated oral doses to human subjects with varying degrees of renal impairment. There was no evidence of reduced drug clearance with reduced renal function after intravenous doses although there appeared to be an increase in the tissue distribution of antibiotic in the body in uremia. After identical multiple oral dosage regimens serum levels of antibiotic were comparable in normal and mildly uremic subjects. There was no evidence of renal toxicity in normal or uremic subjects with the repeated dosage regimen used.     

Pharmacokinetics of Cefamandole in Patients with Renal Failure

The pharmacokinetics of cefamandole were studied in four patients with stable renal failure, two patients undergoing peritoneal dialysis, and four patients undergoing hemodialysis. Peak concentrations of cefamandole in serum were achieved 1 to 2 h after intramuscular injection in the patients with stable renal impairment, and the concentrations declined slowly, with half-life values of 12.3 to 18 h. Cefamandole was removed only very slowly by peritoneal dialysis. Hemodialysis was more efficient in removing cefamandole, with serum half-life values ranging from 3.8 to 7.9 h. The mean apparent volume of distribution of cefamandole in these 10 patients was 21.92 liters, or 31% of the body weight.     

Pharmacokinetics of Nafcillin in Patients with Renal Failure

Nafcillin, a pencillinase-resistant penicillin, is frequently used for treatment of staphylococcal infections in hemodialysis patients. Despite its widespread use, there is a paucity of available data regarding the pharmacokinetics of nafcillin in hemodialysis patients. Therefore, sodium nafcillin, 25 mg/kg, was given intravenously over a 5- to 15-min period to 12 hemodialysis patients. Eleven patients were studied during dialysis, and eight of these were studied again during the interdialysis period. The initial serum half-life for nafcillin was 0.208 h during dialyses and 0.278 h between dialyses. The terminal half-life was 1.48 h during dialyses and 1.89 h between dialyses. There was no statistically significant difference between these values. These data indicate that renal failure does not appreciably affect the serum half-life of nafcillin, and hemodialysis does not accelerate the rate of clearance of nafcillin from the blood. Therefore, no modification of the usual nafcillin dosage is necessary when using this drug in hemodialysis patients.     

Effects of Renal Failure and Dialysis on Cefazolin Pharmacokinetics

Serum and urinary levels of cefazolin were determined after a 500-mg parenteral dose in eight azotemic volunteers. The mean peak serum concentration was 1.5 to 5 times the levels obtained in nonazotemic patients. The serum half-life of cefazolin was increased significantly. In patients on dialysis, the mean serum half-life of cefazolin was 4.05 h during (or after) hemodialysis, and 32.1 h during (or after) peritoneal dialysis. There was a significant decrease in cefazolin removal when dialysate flow or membrane surface area of the dialyzer were decreased. It was also shown that one circuit through the dialysis unit caused measurable decrease in cefazolin concentration. These data and previously published reports suggest: (i) the maintenance dose of cefazolin can be decreased in azotemic patients; (ii) patients on hemodialysis will require an additional half dose after dialysis because of efficient removal during hemodialysis; and (iii) patients on peritoneal dialysis do not require an extra dose.     

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg(minus sign1) as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h(minus sign1) kg(minus sign1) and volume of distribution was about 1.1 L kg(minus sign1). Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC(50)) of methylprednisolone disappear. The difference in IC(50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.     

Pharmacokinetics of Cefaclor in Normal Subjects and Patients with Chronic Renal Failure

We studied the pharmacokinetics of cefaclor, a new cephalosporin antibiotic, in normal subjects and subjects with chronic renal failure. Cefaclor was largely, but not entirely, eliminated by the kidneys. The cefaclor half-life in normal subjects was 40 to 60 min; in subjects with essentially no renal function, it increased to 3 h. In normal subjects, 50 to 70% of a 250-mg dose was excreted in the urine within 8 h. The linear relationship between the elimination constant and creatinine clearance allowed the construction of a useful dosage modification nomogram.     

Pharmacokinetics of a New Carbapenem, DA-1131, after Intravenous Administration to Rats with Uranyl Nitrate-Induced Acute Renal Failure

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug (50 mg/kg of body weight) to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF rats). The impaired kidney function was observed in U-ARF rats on the basis of physiological parameters observed by microscopy of the kidney and obtained by chemical analysis of the plasma. After a 1-min intravenous infusion of DA-1131, the concentrations in plasma and the total area under the plasma concentration-time curve from time zero to time infinity increased significantly in U-ARF rats compared with those in control rats (13,000 versus 4,400 μg · min/ml). This was due to the significantly slower total body clearance (CL) of DA-1131 (3.84 versus 11.4 ml/min/kg) from U-ARF rats than from control rats. The significantly slower CL of DA-1131 from U-ARF rats was due to both significantly slower renal clearance (0.000635 versus 4.95 ml/min/kg because of a significant decrease in the 8-h urinary excretion of unchanged DA-1131 [1.54 versus 43.8% of the intravenous dose] due to impaired kidney function, as proved by the significant decrease in creatinine clearance [0.0159 versus 4.29 ml/min/kg]) and significantly slower nonrenal clearance (3.80 versus 6.34 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney) in U-ARF rats. The amounts of DA-1131 recovered from all tissues studied (except the kidneys) were significantly higher for U-ARF rats than for control rats; however, the ratios of the amount in tissue to the concentration in plasma (except those for the kidney, small intestine, and spleen) were not significantly different between the two groups of rats, indicating that the affinity of DA-1131 for rat tissues was not changed considerably in U-ARF rats.     

Glomerular Endothelial Cells in Uranyl Nitrate-induced Acute Renal Failure in Rats

In uranyl nitrate (UN)-induced acute renal failure (ARF) glomerular ultrafiltration coefficient (K_f) decreases because of unknown reasons. Since transport of water across the glomerular capillary wall occurs predominantly extracellularly through the endothelial fenestrae (EF), a reduction in the diameter and/or the density of EF can reduce the extracellular filtration area and the glomerular K_f. To examine this possibility, ARF was induced in rats by intravenous administration of UN in low (15 mg/kg) and high doses (25 mg/kg). Fenestral density (¯x±SEM) per 5 cm² from the scanning electron micrographs (×30,000) was 107±10, 103±9, and 101±11 at 2, 7, and 17 h after the intravenous administration of bicarbonate saline to the control rats. In the low-dose UN group the EF density was 91±2, 52±8, and 45±11 at 2, 7, and 17 h after the injection, whereas for the high-dose group at corresponding time intervals the EF density was 95±3, 54±9, and 44±10. Fenestral diameters, in Angstrom units (¯x±SEM), were 751±53, 765±43, and 764±37 at 2, 7, and 17 h after the injection of bicarbonate saline to control rats. At corresponding intervals after the administration of UN, the fenestral diameters were 501±61, 472±28, and 438±98 for the low-dose group and 525±43, 470±39, and 440±56 for the high-dose group. 2, 7, and 17 h after the injection of UN, fenestral area of the low-dose group decreased to 52.1, 30.1, and 24.6% of the controls, whereas in the high-dose group, the fenestral area declined to 54.3, 30.2, and 23.6% of the controls. Administration of UN (15 mg/kg) to sodium-loaded rats did not alter renal function or endothelial cell morphology. It is suggested that in UN-induced ARF the morphological alterations in endothelial cells reduce the K_f of glomerular capillaries by reducing the filtration area.     

Pharmacokinetics of Cefamandole in the Presence of Renal Failure and in Patients Undergoing Hemodialysis

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 ± 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 ± 32.0 μg/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 ± 20.8 μg/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.     

The Influence of Misoprostol on the Adverse Renal Effects and Stereospecific Pharmacokinetics of Ibuprofen in Chronic Renal Insufficiency

The use of nonsteroidal anti-inflammatory drugs in patients with chronic renal insufficiency (CRI) may be complicated by renal functional abnormalities due to the inhibition of renal prostaglandins. We tested the hypothesis that administration of the oral PGE1 analog, misoprostol, could attenuate the adverse renal effects of ibuprofen in patients with CRI. Because the metabolism of misoprostol and the stereoinversion of R- to S-ibuprofen involve the same metabolic pathway, the stereospecific pharmacokinetics of ibuprofen were also evaluated. In a randomized, crossover trial of six stable CRI patients (Clcr 25--67 ml min(minus sign1)), in sodium balance on a 150 mEq Na(+) per day metabolic diet, we compared the effects of ibuprofen 600 mg qid with and without misoprostol 200 &mgr;g qid upon Clcr, Clinulin, Clpah, Na(+), and K(+) excretion during 4-h clearance studies. We also assessed stereospecific ibuprofen kinetics following single dose (acute) and after 7 days on drug(s) (chronic). Daily weights, supine blood pressures, electrolytes, osmolality, BUN, creatinine and 24-h urine collections for Clcr and Na(+) and K(+) excretions were obtained during chronic dosing. Supine and upright plasma renin activities were obtained prior to dosing and during chronic dosing for both treatment limbs. Ibuprofen alone resulted in an approximately 20% transient reduction in GFR, occurring 2--2.5 h following dosing in both the acute and chronic clearance studies. This was not affected by misoprostol. There was a greater degree of stimulation of PRA with the upright posture with misoprostol plus ibuprofen than with ibuprofen alone. There was a significant weight gain in both study limbs, but no effect of misoprostol (1.2 plus minus 0.2 kg ibuprofen alone and 1.0 plus minus 0.2 kg ibuprofen plus misoprostol, p = 0.13). Otherwise no clinically significant alteration in renal function occurred in either treatment limb. The presence of misoprostol did not alter the stereospecific pharmacokinetics of ibuprofen. We conclude that misoprostol does not significantly alter the renal effects of ibuprofen in patients with mild to moderate CRI.     

Pharmacokinetic-Pharmacodynamic Modeling of Electroencephalogram Effect of Imipenem in Rats with Acute Renal Failure

The epileptogenic activity of imipenem was investigated in rats with experimental renal failure induced by uranyl nitrate injection by using electroencephalogram (EEG) recording and a pharmacokinetic-pharmacodynamic model including an effect compartment. Results previously obtained with healthy rats were used to estimate the dose of imipenem required to induce an observable but nonlethal EEG effect on the assumption that only the pharmacokinetic parameters of the model would be affected by renal failure. Good agreement was observed between the predicted and observed effects.     

Pharmacokinetics of Meropenem in Critically Ill Patients with Acute Renal Failure Treated by Continuous Hemodiafiltration

The pharmacokinetics of meropenem were studied in nine anuric critically ill patients treated by continuous venovenous hemodiafiltration. Peak levels after infusion of 1,000 mg over 30 min amounted to 103.2 ± 45.9 μg/ml, and trough levels at 12 h were 9.6 ± 3.8 μg/ml. A dosage of 1,000 mg of meropenem twice a day provides plasma drug levels covering intermediately susceptible microorganisms. Further reductions of the dosage might be appropriate for highly susceptible bacteria or when renal replacement therapies with lower clearances are applied.     

Renal Failure

Modern methods of treatment of acute and chronic renal failure are much improved over those of 10 years ago, but before vigorous treatment is instituted one must be sure it is given by the right hands in the right manner.

Dialysis with the artificial kidney may be lifesaving and should be employed earlier when indicated. Use of the artificial kidney is not simply a matter of having the unit available; it also requires highly trained personnel.

Many lives could also be saved by preventing renal failure. Important points in recognizing impending failure are stressed.

In chronic renal failure, synthetic diets provide for accurate regulation of nutrients. The “antipotassium cocktail” is helpful in preventing potassium intoxication, as are the potassium-binding resins.     

The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.     

阿魏酸钠对慢性肾功能衰竭患者尿蛋白的影响

将 40例慢性肾功能衰竭 (CRF)患者随机分为对照组 (n =2 0 )和治疗组 (n =2 0 )进行 4周治疗观察。结果对照组和治疗组2 4小时尿蛋白 ( 2 4hUPE)、Scr、BUN均有所下降 ,Ccr有所升高 ,但只有治疗组 2 4hUPE、BUN下降明显 (P <0 .0 5 ) ,对照组和治疗组其余各项变化均不明显 (P >0 .0 5 )。阿魏酸钠对CRF氮质血症期的尿蛋白有治疗作用。     

造影剂致原有肾损害大白鼠急性肾衰的病理生理及病理学研究

研究了造影剂对甘油致肾损害大白鼠的肾毒性。结果示：注射造影剂后２４ｈ，尿γ谷氨酰转肽酶（γ－ＧＴ）、尿蛋白显著增高（Ｐ＜０．０５）；７２ｈ，尿γ－ＧＴ开始恢复，血清尿素氮和血清肌酐显著增高（Ｐ＜０．０１），肾组织肿瘤坏死因子无明显改变，组织学可见肾小管上皮细胞和肾小球损害，肾小管腔阻塞。提示造影剂肾毒性的发病机理可能与直接肾毒性及肾小管阻塞有关。并对尿γ－ＧＴ影响因素进行探讨。     

Pharmacokinetics of Itraconazole in Diabetic Rats

After intravenous or oral administration of 10 mg/kg itraconazole to rats with streptozotocin-induced diabetes mellitus and to control rats, the total area under the plasma concentration-time curve from time 0 to 24 h (AUC_0-24) for itraconazole and that for its metabolite, 7-hydroxyitraconazole, were similar between the two groups of rats. This may be explained by the comparable hepatic and intestinal intrinsic clearance rates for the disappearance of itraconazole and the formation of 7-hydroxyitraconazole in both groups of rats.Itraconazole is a prototype triazole antifungal agent. Superficial fungal infections of the feet among elderly patients with diabetes mellitus are common, and itraconazole has been shown to have acceptable cure rates (12). In humans, hepatic cytochrome P450 3A4 (CYP3A4) appears to be involved in the metabolism of itraconazole to form several metabolites, including 7-hydroxyitraconazole (9). No in vivo studies of itraconazole metabolism in rats have been reported. Hepatic CYP3A1 (5) and CYP3A2 (10) proteins and/or mRNA levels have been shown to increase in male Sprague-Dawley rats with diabetes mellitus induced by streptozotocin (DMIS rats), but there are no reports on the intestinal CYP3A subfamily in DMIS rats. Furthermore, the pharmacokinetics of itraconazole and 7-hydroxyitraconazole may differ between intravenously and orally administered itraconazole in DMIS rats.In the present study, itraconazole metabolism was examined in DMIS rats as an animal model of diabetes mellitus. We report the pharmacokinetics of itraconazole and 7-hydroxyitraconazole after intravenous or oral administration in DMIS rats compared with those in control rats. Our results show that hepatic CYP3A1/2 is responsible for the metabolism of itraconazole and the formation of 7-hydroxyitraconazole in rats and that the expression of the intestinal CYP3A1/2 protein was not altered in DMIS rats compared with that in control rats, based on Western blot analysis.Overall, the methods used in this study were similar to those described in previous reports. The chemicals used in addition to itraconazole, the methods of housing and handling the male Sprague-Dawley rats (7 to 9 weeks old, weighing 230 to 280 g), the intravenous and oral administration of itraconazole, the measurement of plasma protein binding values of itraconazole by equilibrium dialysis, and the high-performance liquid chromatographic analysis of itraconazole and 7-hydroxyitraconazole were all performed as described previously (1, 11). Dia-betes mellitus was induced with streptozotocin (5). Seven control rats and eight DMIS rats were used in the intravenous administration study. Nine control rats and nine DMIS rats were used in the oral study. Intravenous administration of itraconazole to control rats pretreated with dexamethasone and troleandomycin was performed as previously described (3). Hepatic and intestinal microsomes were prepared from control and DMIS rats (6). The protein expression of intestinal CYP3A1/2 was examined by Western blot analysis (7).The procedures for measuring V_max and K_m for the disappearance of itraconazole and the formation of 7-hydroxyitraconazole were similar to those used in a previous report (6). Microsomes (equivalent to 0.5 mg protein); 5 μl of dimethyl sulfoxide containing 2.5, 5, 10, 20, 30, or 50 μM itraconazole; and 50 μl of 0.1 M phosphate buffer (pH 7.4) containing 1 mM NADPH were mixed and incubated for 0, 15, 30, 45, or 60 min for hepatic microsomes or for 5, 15, 30, 45, 60, or 75 min for intestinal microsomes. All microsomal incubation conditions were within the linear range of the reaction. After incubation for 45 min (for hepatic microsomes) or 50 min (for intestinal microsomes), 100 μl of each reaction mixture was transferred to a test tube containing 100 μg/ml {"type":"entrez-nucleotide","attrs":{"text":"R51012","term_id":"812914","term_text":"R51012"}}R51012 (internal standard) in 50 μl of acetonitrile, 250 μl of 0.1 M carbonate buffer (pH 9.8), and 1 ml of methyl t-butyl ether. The kinetic constants (K_m and V_max) were calculated using a nonlinear regression method (4). Intrinsic clearance (CL_int) was calculated by dividing V_max by K_m.The total area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞) or from time 0 to the last measured time at 24 h (AUC_0-24) was calculated using the trapezoidal rule-extrapolation method (2). The peak plasma concentration (C_max) and time needed to reach C_max (T_max) were directly read from the experimental data. The percentage of the dose excreted in a 24-h urine sample (Ae_0-24) and that recovered from the gastrointestinal tract (including its contents and feces) sampled after 24 h (GI_0-24) were also measured (11). All results are expressed as mean values ± standard deviations, with the exception of values for T_max, which are expressed as median values with ranges. Unpaired t tests were performed, and P values of <0.05 were regarded as statistically significant.Plasma protein binding values of itraconazole at 5 μg/ml were similar between the control (97.9% ± 0.242%) and DMIS (97.9% ± 0.137%) rats (n = 4 for each). The protein expression of intestinal CYP3A1/2, as determined by Western blot analysis, did not differ between the two groups of rats (n = 3 for each) (data not shown). Furthermore, K_m, V_max, and CL_int values for the disappearance of itraconazole and the formation of 7-hydroxyitraconazole in both hepatic and intestinal microsomes (n = 4) were comparable between the control and DMIS rats (Table ​(Table11).

TABLE 1.

V_max, K_m, and CL_int values for the disappearance of itraconazole and formation of 7-hydroxyitraconazole in hepatic and intestinal microsomes from control and DMIS rats

红细胞生成素受体mRNA在慢性肾功能衰竭大鼠骨髓细胞中表达减少

采用RT-PCR方法观察次全肾切除大鼠的骨髓细胞中红细胞生成素(EPO)受体mRNA表达的变化,结果发现急性贫血可使骨髓细胞中EPO受体mRNA表达显著增多,而次全肾切除大鼠的骨髓细胞中EPO受体mRNA表达显著减少。结论表明,慢性肾功能衰竭能明显抑制EPO受体基因表达,提示这一作用参与慢性肾功能衰竭贫血的发生。