Pharmacokinetics of cefotiam in patients with impaired renal function and in those undergoing hemodialysis.

The pharmacokinetics of cefotiam were studied after a single intravenous 1.0-g dose to 18 subjects grouped according to their creatinine clearances (CLCR); CLCR was above 75, 75 to 20, and below 20 ml/min per 1.73 m2 in groups 1, 2, and 3, respectively. Cefotiam obeyed two-compartment model kinetics in all three groups. The volume of distribution based on the area under serum concentration-time curve (Varea) was renal function independent, the average value being 0.350 +/- 0.159 liters/kg. The elimination-phase half-life (t1/2 beta) was 0.916 +/- 0.090 h in group 1, 2.03 +/- 1.62 h in group 2, and 7.09 +/- 3.06 h in group 3. Cumulative 24-h urinary excretion accounted for 65 to 93% of the dose in four subjects with CLCRS above 80 ml/min per 1.73 m2 and 19 to 41% in three subjects with CLCRS below 20 ml/min per 1.73 m2. We give recommendations for dosage adjustment in patients with renal insufficiency. The effect of hemodialysis on cefotiam pharmacokinetics was studied in six patients in end-stage renal failure; hemodialysis shortened the average t1/2 beta from 8.02 +/- 4.04 h to 2.74 +/- 2.15 h. We estimated that in a hypothetical anephric patient with a body weight of 60 kg, 6-h hemodialysis would remove 49.7% of the drug present in the body at the start of dialysis.     

Kinetic interactions between azlocillin, cefotaxime, and cefotaxime metabolites in normal and impaired renal function

Cefotaxime (CTX) kinetics, alone and in combination with azlocillin (AZ), were determined in 18 subjects with either normal or impaired renal function. After the single dose and with increasing renal insufficiency, total CTX clearance fell from 266 to 71 ml/min/1.73 m2. At the same time the terminal t1/2 rose from 1.1 to 2.8 hr. Regardless of the degree of renal function, CTX clearance in combination with AZ in all patients was only 50% to 60% of that with CTX alone. This reduction in total body clearance was due to a parallel decrease in renal and nonrenal clearance. In advanced renal failure, particularly after AZ, the terminal t1/2 of the CTX metabolites increased up to 1000% to 1500% of normal. On the basis of these findings, CTX dosage adjustment is recommended only in patients with a glomerular filtration rate (GFR) below 20 ml/min. After AZ, however, dosage reduction of CTX seems to be advisable at an earlier stage of renal impairment (GFR 40 ml/min).     

Pharmacokinetics of cefonicid in uraemic patients

Eight subjects with normal renal function and 20 uraemic patients with various degrees of renal insufficiency were given a single iv dose of 1.0 g cefonicid, as a bolus injection. Five groups of subjects were studied: group I, GFR greater than 80 ml/min, group II 30 less than GFR less than 80 ml/min, group III 10 less than GFR less than 30 ml/min, group IV GFR less than or equal to 10 ml/min and group V, haemodialysis patients. Cefonicid concentrations in plasma and urine were measured by microbiological assay (MA) and HPLC method. Results were similar with the two techniques. The mean peak plasma levels were 200-300 mg/l and the apparent volume of distribution was 0.18-0.20 1/kg for all patients. The elimination half-life (T 1(2) beta) increased as renal function decreased: 5.31 +/- 1.30 h in healthy subjects and 58.92 +/- 12.38 h in patients with end-stage renal disease. Urinary elimination of cefonicid was inversely related to the degree of renal impairment: 83% of the dose in 24 h in normal subjects and 13.6% of the dose in patients with severe renal failure. Total body clearance decreased from 23.9 +/- 3.4 ml/min/1.73 m2 (group I) to 1.9 +/- 0.2 ml/min/1.73 m2 (group V). Renal clearance fell from 19.0 +/- 4.9 ml/min/1.73 m2 (group I) to 1.0 +/- 0.4 ml/min/1.73 m2 (group IV). The fractional clearance and the non renal clearance were similar in normal subjects and in uraemic patients. Cefonicid is not haemodializable because of its high protein binding. Dosage of cefonicid should be adjusted according to the degree of renal impairment. Supplemental doses are not necessary after haemodialysis.     

Clinical pharmacology of trimetrexate

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.     

Differential effect of impaired renal function on the kinetics of clavulanic acid and amoxicillin.

Amoxicillin and clavulanic acid are prescribed as a fixed drug combination. The purpose of the present study was to assess the influence of various degrees of renal insufficiency (glomerular filtration rate [GFR], less than 5 to greater than 75 ml/min per 1.73 m2) on the pharmacokinetics of amoxicillin and clavulanic acid following oral (500 and 125 mg of amoxicillin and clavulanic acid, respectively) and intravenous (1,000 and 200 mg, respectively) dosing. The volume of distribution and the systemic availability were independent of the renal function, while the total body clearance and the renal and the nonrenal clearance of amoxicillin and clavulanic acid decreased with decreasing renal function. The decrease in the total body clearance was more pronounced for amoxicillin than for clavulanic acid. This explains the increase in the ratio of the area under the plasma concentration versus time curve of amoxicillin to that of clavulanic acid with decreasing glomerular filtration rate after oral dosing; for example for a GFR of 75 ml/min, the ratio of amoxicillin to clavulanic acid was 4.9 +/- 1.2; for a GFR of 35 to 75 ml/min, 5.3 +/- 2.4; for a GFR of 10 to 35 ml/min, 11.9 +/- 5.8; for a GFR of 5 to 10 ml/min, 13.4 +/- 9.1; and for patients on hemodialysis, 14.7 +/- 5.3. Dosage recommendations are suggested which prevent undue accumulations of amoxicillin while maintaining adequate concentrations of clavulanic acid.     

Pharmacokinetics of CaNa2EDTA and chelation of lead in renal failure

The pharmacokinetics of 1 gm intramuscular doses of CaNa2 (14C-)EDTA and the chelation of lead (Pb) were studied in 10 subjects with varying degrees of renal function and normal body burdens of Pb. The clearance of CaNa2EDTA significantly correlated with creatinine clearances (CLCR) (r = 0.8373; P = 0.0097). Clearances were decreased in subjects with CLCR less than 70 ml/min as compared with subjects with CLCR greater than 100 ml/min (28 vs. 76 ml/min). Maximum serum CaNa2EDTA concentrations and volume of distribution (Varea) (0.05 to 0.23 L/kg) were similar in all subjects. The Varea is smaller than previously described and is more consistent with other experimental data. Considering all subjects, initial blood Pb concentrations correlated with cumulative urine Pb excretion over 3 days (r = 0.8967; P = 0.0005). Urine Pb excretion did not correlate with measures of renal function or measures of CaNa2EDTA kinetics. Subjects with abnormal CLCR showed significantly greater decreases in blood Pb from day 1 to day 4 (7.0 micrograms/dl vs. 1.2 micrograms/dl) compared with normal subjects. These decreases in blood Pb correlated with CLCR (r = 0.7774; P = 0.138) and urine protein (r = 0.8435; P = 0.0087) but not with urine Pb excretion. Renal dysfunction may alter Pb chelatability, bone-blood Pb reequilibration, PbEDTA distribution, or PbEDTA excretion.     

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

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 (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min 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 greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 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 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 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.     

Cefmenoxime pharmacokinetics in patients with renal insufficiency.

The pharmacokinetics of cefmenoxime were determined after a 30-min intravenous infusion of 15 mg/kg of total body weight to 33 adult subjects with normal renal function (CLCR, greater than 80 ml/min per 1.73 m2, group I), mild renal insufficiency (CLCR, 40 to 79 ml/min per 1.73 m2, group II), moderate renal insufficiency (CLCR, 10 to 39 ml/min per 1.73 m2, group III), or severe renal impairment, (CLCR, less than 10 ml/min per 1.73 m2, group IV) or to patients between hemodialysis (CLCR, less than 10 ml/min per 1.73 m2, group V). Concentrations of cefmenoxime in serum and urine were determined by high-pressure liquid chromatography, and serum concentrations were fit to a two-compartment model. There was no significant relationship between creatinine clearance and either peak serum concentrations or volume of distribution at steady state. Patients in group I excreted 81% of the dose into the urine within 24 h; recovery decreased with worsening renal function. The mean terminal half-lives in groups I to V were 1.06, 1.50, 3.55, 4.60, and 11.4 h, respectively. There were good linear relationships between creatinine clearance, and the elimination rate and total body clearance of cefmenoxime. Dosage recommendations for subjects with renal insufficiency are proposed.     

肾动态显像前位采集测定肾脏前移患者肾小球滤过率的可行性

目的探讨单侧肾脏前移患者肾动态显像前位采集测定肾小球滤过率(glomerular filtration rate,GFR)的可行性和准确性。方法选择2017年8月至2021年12月于复旦大学附属中山医院核医学科行肾动态显像，并通过Gates法测定GFR的单侧肾脏前移患者22例，同时进行前位和后位图像采集，并使用后位图像处理双肾数据，使用前位图像处理前移单肾数据，计算相应GFR值。健侧肾后位采集测定的GFR值与前移肾前位采集测定的GFR值之和记作GFR_优化；常规后位采集测定的双肾GFR值之和记作GFR_常规。采用慢性肾脏病流行病学协作组(Chronic Kidney Disease Epidemiology Collaboration,CKD-EPI)推荐的基于血清肌酐(serum creatinine,sCr)方程计算的估算GFR(estimated GFR,eGFR)作为参照值，比较GFR_优化、GFR_常规与eGFR的差异，并进行Pearson相关性分析。结果22例患者前移单肾的前位肾脏深度显著小于后...     

Association between glomerular filtration rate and extracellular fluid volume in normal subjects and patients with renal impairment

The aim of the study was to determine the extent to which glomerular filtration rate (GFR) measured with one filtration marker is associated with extracellular fluid volume (ECV) measured independently with another. Cr-51-EDTA and iohexol were injected simultaneously into opposite arms in 20 normal volunteers and 60 patients. Cubital samples taken bilaterally at 20, 40, 60, 120, 180 and 240 min were assayed for marker injected contralaterally. GFR was scaled to body surface area of 1.73 m(2) (GFR/BSA). GFR was also expressed as marker transit time (GFR/ECV) and ECV as the product of marker transit time and GFR/BSA. In normal subjects, changes between fasting and non-fasting ECV/BSA correlated positively with changes in GFR/BSA, but not GFR/ECV. GFR/BSA and GFR/ECV correlated positively (regression slope approximately 4 ml.min(-1).litre(-1)) and negatively (-2.7 ml x min(-1) x litre(-1)), respectively, with ECV/BSA. The difference, 6.7 ml x min(-1) x litre(-1), expressed as a fraction of average scaled GFR ( approximately 90 ml x min(-1)) is close to the reciprocal of average ECV/BSA (13.5 litres.1.73 m(-2)), consistent with the expected slope of the regression on ECV/BSA of the difference-to-average ratio of GFR/BSA and GFR/ECV. In contrast, in 29 patients with impaired GFR (estimated from plasma creatinine), ECV/BSA correlated inversely with GFR/ECV (slope approximately -5 ml x min(-1) x litre(-1)) but showed no relation with GFR/BSA. We conclude that in normal subjects GFR/BSA increases in response to increasing ECV/BSA, but the increase is not proportionate, leading to a weak inverse association between GFR/ECV and ECV/BSA. When ECV is expanded in patients with renal impairment, however, there is no GFR response, leading to a reduction in GFR/ECV.     

Trazodone kinetics: effect of age, gender, and obesity

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.     

Pharmacokinetics of cefepime dihydrochloride arginine in subjects with renal impairment.

In this study, the safety, tolerance, and pharmacokinetics of a single 1-g intravenous dose of cefepime (BMY-28142) were investigated. Twenty-three volunteers with various degrees of renal function were assigned to four trial groups according to glomerular filtration rates (GFR). Group IV consisted of five patients with end-stage renal disease undergoing treatment with hemodialysis. Cefepime concentrations in samples from plasma, urine, and infusion solutions were assayed with high-pressure liquid chromatography. The volume of distribution corresponded to the assumed extracellular fluid volume and did not differ significantly between the four groups. The area under the concentration-time curve increased as renal function decreased; in group II (GFR, 31 to 80 ml/[min x 1.73 m2]; n = 6), it was already three times higher than in group I (GFR, > or = 80 ml/[min x 1.73 m2]; n = 5). Mean residence time was 2.4, 6.8, 11.4, and 31.6 h for the four groups, respectively. Total clearance decreased (97.2, 34.6, 19.8, and 6.3 ml/[min x 1.73 m2]) with decreasing renal function, and a linear relationship between total plasma clearance and GFR was found with the regression equation y = 0.92x-2.0 (r = 0.991). Renal clearance was linearly correlated to GFR with the regression equation y = 0.87x-6.1 (r = 0.989), indicating that renal elimination is mainly by glomerular filtration. During hemodialysis, the extraction ratios were between 0.40 and 0.65. Dialysis clearance varied between 69.9 and 94.6 ml/(min x 1.73 m2).     

Effects of impaired renal function, hemodialysis, and peritoneal dialysis on the pharmacokinetics of mezlocillin

The pharmacokinetics of mezlocillin were examined in 8 patients with normal renal function (inulin clearance, > 80 ml/min per 1.73 m2), 32 patients with moderately reduced renal function (inulin clearances, 80 to 5 ml/min per 1.73 m2), and 12 patients maintained by hemodialysis or peritoneal dialysis because of severely impaired renal function. A single dose of 60 mg of mezlocillin per kg of body weight was infused intravenously over 30 min. Antibiotic concentrations in plasma, urine, and dialysate were determined by the agar diffusion technique. The half-life of mezlocillin increased with decreasing renal function from an average of 53 min in subjects with normal function to 165 min in oligoanuric patients. The urinary recovery of this drug in 24 h decreased from 65% at a glomerular filtration rate of 92 ml/min to 7.6% at a glomerular filtration rate of 6.7 ml/min. Volume of distribution was not changed by the renal insufficiency, amounting on the average to 22.5% of body weight. Intermittent hemodialysis or peritoneal dialysis contributed to only a minor degree to the 24-h mezlocillin kinetics. The pharmacokinetic properties of mezlocillin permit a normal dosage over wide ranges of renal insufficiency; however, when the glomerular filtration rate is below 10 ml/min, the dosage interval should be increased from 8 to 12 h.     

Enhancement of glomerular filtration rate and renal plasma flow by oral glucose load in well controlled insulin-dependent diabetics

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured in 27 patients with uncomplicated insulin-dependent diabetes (IDDM) before and after an oral glucose load of 1.1 g glucose/kg body wt. In the 18 patients showing near-normoglycaemia (blood glucose less than or equal to 8 mmol/l) before the glucose challenge the increase in blood glucose from 4.2 +/- 1.7 to 15.2 +/- 2.3 mmol/l was accompanied by an enhancement of GFR from 128 +/- 15 to 132 +/- 14 ml/min X 1.73 m2 (2p = 0.030) and of RPF from 534 +/- 116 to 562 +/- 105 ml/min X 1.73 m2 (2p = 0.023). By contrast oral glucose load to the nine patients with hyperglycaemia (greater than 8 mmol/l) during baseline conditions raising blood glucose from 11.9 +/- 2.0 to 19.6 +/- 1.5 mmol/l was accompanied by a reduction in GFR from 149 +/- 15 to 139 +/- 9 ml/min X 1.73 m2 (2p less than 0.001) while RPF was unchanged. No changes in blood pressure or urinary albumin excretion rates took place in either group. The reduction in plasma protein and in plasma growth hormone concentration were similar in the two groups. No change was seen in plasma arginine vasopressin concentration. There was no difference in the qualitative GFR response in patients with high initial GFR values (greater than or equal to 130 ml/min X 1.73 m2) as compared to patients with initial values below 130 ml/min X 1.73 m2. It is concluded that the induction of moderate hyperglycaemia in IDDM patients is followed by an enhancement of GFR and RPF-provided near-normoglycaemia before the glucose challenge.     

Renal haemodynamics during propranolol treatment in patients with arterial hypertension and chronic renal failure

The effect of propranolol on renal haemodynamics was studied in nine patients with arterial hypertension and moderate to severe chronic renal failure. A reduction of the renal function in this type of patient might have clinical consequence. The patients, whose glomerular filtration rate (GFR) ranged between 17 ml/min/1.73 m2 and 71 ml/min/1.73 m2, were studied during three 4-week periods with alternately placebo, propranolol (40 mg b.i.d.) and placebo treatment. The GFR and the effective renal plasma flow (ERPF) were determined as the plasma clearance of 51Cr-EDTA and 125I-hippurane. The GFR fell on the average 7% (95% confidence limits: 1-12%) during propranolol treatment, and the fall was reversible. No changes were found in ERPF. In conclusion, propranolol treatment in this type of patient causes a modest and reversible fall of GFR.     

Cefotaxime and desacetyl cefotaxime kinetics in renal impairment

Cefotaxime and desacetyl cefotaxime kinetics after a single, 1 gm intravenous dose were evaluated in five groups of subjects: group I, normal creatinine clearance (CLCR greater than 90 ml/min); group II, mild renal insufficiency (CLCR 30 to 89 ml/min); group III, moderate renal insufficiency (CLCR 16 to 29 ml/min); group IV, severe renal insufficiency (CLCR 4 to 15 ml/min); and group V, end-stage renal disease requiring maintenance hemodialysis (CLCR less than 6 ml/min). The steady-state volume of distribution (Vss) ranged from 10% to 55% of body weight but was not related to CLCR. The terminal t1/2 values of cefotaxime and desacetyl cefotaxime were 0.79 and 0.70, 1.09 and 3.95, 1.55 and 5.65, 2.54 and 14.23, and 1.63 and 23.15 hours in groups I to V, respectively. There were no significant changes in Vss or t1/2 after multiple dosing, but there were significant correlations between CLCR and cefotaxime total body clearance, cefotaxime and desacetyl cefotaxime renal clearance, and cefotaxime nonrenal clearance. Dosage regimens for the use of cefotaxime in patients with renal impairment are proposed.     

Cefoxitin pharmacokinetics: relation to three different renal clearance studies in patients with various degrees of renal insufficiency.

The pharmacokinetics of cefoxitin were examined in 4 healthy volunteers, 6 patients with normal renal function (inulin clearance, greater than 80 ml/min per 1.73 m2), and 35 patients with various degrees of renal insufficiency (inulin clearance, 80 to less than 5 ml/min per 1.73 m2). A single dose of 30 mg of cefoxitin per kg of body weight was injected intravenously over 3 min. Antibiotic concentrations in plasma were determined by the agar diffusion technique. The cefoxitin half-life increased progressively from 39 min in subjects with normal renal function to 23.5 h in oligoanuric patients. Correspondingly, total body clearance decreased from 340 to 13 ml/min per 1.73 m2. In addition to the study of cefoxitin kinetics, in 29 of the 41 patients, three different renal clearance tests were performed (inulin, p-aminohippurate, and creatinine clearances). Of these, p-aminohippurate clearance showed the best correlation with the elimination rate constant beta as well as total body clearance of cefoxitin; but with respect to beta, the differences between the p-aminohippurate and creatinine clearances were quantitatively negligible. Therefore, even in substances which are eliminated predominantly by active tubular secretion, creatinine clearance could be recommended for dosage adjustments.     

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.     

Pharmacokinetics of mezlocillin in patients with kidney impairment: special reference to hemodialysis and dosage adjustments in relation to renal function

The pharmacokinetics of Mezlocillin were determined after the intramuscular injection of a single 1-gram dose in 10 subjects with normal renal function, in 10 patients with stabilized renal impairment and in 5 patients with end-stage renal disease submitted to repeated hemodialysis. In normal subjects, biological half-life, Tb1/2, was equal to 0.9 h; total clearance (Ct) to 449 ml/min/1.73 m2; renal clearance (Cr) to 263 ml/min/1.73 m2.72.2% of the administered dose was excreted in the urine within 12 h. In patients with renal insufficiency and in patients undergoing long-term hemodialysis, the serum concentration decrease was markedly slower. During a 6-hour dialysis session, 62% of the Mezlocillin present in the central compartment at the start of hemodialysis was removed. In the 25 subjects under study, a significant correlation was found between the values of Ke and those of creatinine clearance, Ccr (Ke = 0.1973+0.0046 Ccr). This relation was used to calculate the loading doses, the maintenance doses and the dosage intervals adjusted to the degree of renal impairment, allowing assessment of useful dosage recommendations.     

Relationship between glomerular filtration rate and the adipokines adiponectin, resistin and leptin in coronary patients with predominantly normal or mildly impaired renal function

BACKGROUND: Due to their molecular weight, it is possible that the adipokines adiponectin, resistin and leptin accumulate when glomerular filtration rate (GFR) is decreased. In reduced renal clearance, altered serum concentrations of these proteins might affect cardiovascular risk. The objective of the study was to investigate the relationship between adipokine concentrations and GFR. METHODS: The association between GFR, as determined by the abbreviated MDRD equation, and the concentrations of the adipokines adiponectin, resistin and leptin was assessed in a cohort of coronary patients (n=538; 363 male, 165 female). After calculation of correlations between GFR and adipokine concentrations, the association was further assessed by analysis of covariance following adjustment for age, gender, BMI, presence of type 2 diabetes, presence of hypertension, history of smoking as well as for serum lipid concentrations. RESULTS: Mean GFR in our study population was 68.74+/-15.27 ml/min/1.73 m(2). 74.3% of the patients had a GFR >60 ml/min/1.73 m(2), 24% of the patients had a GFR between 30 and 60 ml/min/1.73 m(2), and 1.7% of the patients had a GFR <30 ml/min/1.73 m(2). There were significant inverse correlations between adiponectin (r=-0.372; p<0.001), resistin (r=-0.227; p<0.001) and leptin (r=-0.151; p=0.009) concentrations and GFR. After multivariate adjustment, the associations remained significant for adiponectin and resistin. Subgroup analysis in patients with GFR >60 ml/min/1.73 m(2) showed a significant correlation between GFR and adiponectin as well as leptin concentrations. However, after adjustment, these associations no longer were significant. CONCLUSIONS: There is an independent association between GFR and the serum concentrations of adiponectin and resistin. However, this association is not present at GFR >60 ml/min/1.73 m(2). This finding suggests that adipokine concentrations in mildly impaired and normal renal function are influenced by factors other than GFR.