Average Renal Clearance Research Articles

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

A Pharmacokinetic & Pharmacodynamic Study of Oral Lenalidomide in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndromes.

Twelve patients diagnosed with low- or intermediate-1-risk myelodysplastic syndromes (MDS) were administered a single, 10 mg dose of lenalidomide followed by 24-hour blood and urine sampling on one occasion, and again at Day 14 of multiple dosing, followed by 5-hours of blood and urine sampling. Patients then continued into a combined treatment phase in which recombinant EPO was administered with lenalidomide. Table 1 describes the pharmacokinetic profiles of lenalidomide found for the first 12 MDS patients.Following the single oral 10 mg dose, lenalidomide had an average renal clearance of 7.48 ± 1.74 L/hr. Greater than half of the dose (65.6% ± 6.9%) was excreted unchanged in the urine over 24 hours.Conclusions: Among these MDS patients, the single and multiple dose pharmacokinetics of lenalidomide were similar, suggesting no accumulation of lenalidomide with multiple dosing. After 24 hours, 65.6% of the dose is eliminated in the urine as the parent compound. No relationship was apparent between the total number of adverse events normalized per day or Grade's 3+4 adverse events and the drug exposure.Table 1Pharmacokinetics (Mean ± SD) in MDS Patients After a Single and Multiple 10 mg Oral Dose of LenalidomideParameterSingle DoseMultiple DoseCmax1188 ± 59.5168 ± 55.4AUCt852.3 ± 272NAAUCss,0–5NA553.1 ± 205.6T½,z3.72 ± 0.75NAtmax1,21.00 (0.5, 2.00)0.75 (0.75, 2.50)1Cmax and tmax are presented on Day 142median (min, max); NA = Not Applicable

Pharmacokinetics of 2’,3’-Dideoxy-5-fluoro-3’-thiacytidine in Rats

Although several drugs have shown clinical anti-human immunodeficiency virus activity, reduced activity with long-term use and toxicity make new agents with high therapeutic indices desirable. Racemic cis-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) is a new synthetic nucleoside analogue that is usually potent against human immunodeficiency virus types 1 and 2 and hepatitis B virus in vitro. The purpose of this study was to characterize the preclinical pharmacokinetics of FTC in rats. Rats were administered 10, 50, and 100 mg of FTC per kg of body weight intravenously. Concentrations of FTC in plasma and urine were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma FTC concentrations declined rapidly in a biexponential fashion, with a terminal half-life of approximately 2 h. The area under the plasma FTC concentration-time curve increased proportionally with increasing dose, and there were no statistically significant differences in pharmacokinetic parameters among the three doses. Thus, the disposition of FTC was independent of dose over the range of 10-100 mg/kg. Since the disposition of FTC was linear, pharmacokinetic parameters were averaged for the three doses. The average total clearance of FTC was 1.91 +/- 0.32 L/h/kg (mean +/- SD), the average renal clearance was 1.08 +/- 0.26 L/h/kg, and the average nonrenal clearance was 0.83 +/- 0.27 L/h/kg. Approximately 55% of the dose of FTC was recovered as unchanged drug in the urine. The steady-state volume of distribution of FTC averaged 2.17 +/- 0.59 L/kg.

Clearance of Phenylethylmalonamide During Haemodialysis of a Patient with Renal Failure

Information is presented for the serum concentrations during haemodialysis of primidone, phenobarbitone, and phenylethylmalonamide (PEMA) in a patient with renal failure receiving chronic primidone therapy. The concentrations of drug and metabolites fell during haemodialysis, but PEMA concentrations were above normal at all times. The average renal clearance of PEMA during 6 h of dialysis was found to be 84.7 +/- 4.6 ml min-1.

Effect of dose on serum pharmacokinetics of intravenous ciprofloxacin with identification and characterization of extravascular compartments using noncompartmental and compartmental pharmacokinetic models.

The effect of dose on the pharmacokinetics of ciprofloxacin in serum and urine following single intravenous doses of 100, 150, and 200 mg was studied in nine healthy volunteers. Mean peak levels in serum were 1.4, 2.0, and 3.2 mg/liter for the 100-, 150-, and 200-mg doses, respectively. The data on concentrations in serum were best described by a three-compartment pharmacokinetic model. The terminal half-life (from noncompartmental analysis) averaged between 4.2 and 4.6 h. Average urinary recovery ranged between 45.8 and 48.1%. The average renal clearance of ciprofloxacin was 2.9- to 3.4-fold greater than the measured creatinine clearance. Total serum and renal clearances decreased with increasing dose; however, this was not statistically significant (P greater than 0.05; repeated-measures analysis of variance). Ciprofloxacin was well tolerated by all subjects. In this dose range, ciprofloxacin pharmacokinetics are independent of dose.

Lithium: long-term effects on the kidney. IV. Renal lithium clearance.

Renal lithium clearance was investigated in 44 patients treated with lithium for an average of 8 years as part of a functional-morphological follow-up study including a kidney biopsy. The average renal lithium clearance was 0.36 ml/s (= 21.6 ml/min). A significant correlation with age, sex and glomerular filtration rate was seen, whereas no significant relationship with urine volume, lithium treatment regimen and histopathological biopsy variables was found. The results were compared with the same renal functional tests obtained from a control group consisting of 26 patients with affective disorders never treated with lithium. The control group had a lower urine output, but no significant difference in lithium clearance was observed. In conclusion, renal lithium clearance is a specific investigation, which may provide valuable baseline information on glomerulo-tubular function in patients before and during prophylactic lithium treatment.

Reduced ability to clear ultrafilterable platinum with repeated courses of cisplatin.

Ultrafilterable plasma and urinary levels of platinum were quantitated for 24 hours after the first- and fourth-course infusion of cisplatin (CDDP) to seven patients. Four patients received 80 mg/m2 and three patients received 100 mg/m2 CDDP as a 2-hour infusion. The area under the curve (AUC) of ultrafilterable platinum, average renal clearance (CIR) of ultrafilterable platinum, and percentage of the platinum dose excreted in urine (% E) were determined for each infusion over the 26-hour period of the study. The AUC was higher in all patients after the fourth-course infusion, with a median increase of 74%. The median CLR was 494 mL/min (range, 214 to 996 mL/min) for the first course and decreased to 156 mL/min (range, 108 to 271 mL/min) for the fourth-course infusion (P less than .02). The median % E was 29.2% (range, 19.6% to 37.7%) for the first course and decreased to 19.9% (range, 12.4% to 25.9%) for the fourth-course infusion (P less than .02). There was no difference in creatinine clearance for the two infusions (median, 94 mL/min; P greater than .05). Urinary excretion of B2-microglobulin (B2-MG) and N-acetyl-B-glucosaminidase (NAG) was highly variable between patients and did not provide a useful predictor of changes in renal function. Four courses of CDDP therapy resulted in significantly reduced renal elimination of platinum in patients, probably through a reduction in the secretion of the drug in the proximal tubule of the kidney. The results suggest that increased antitumor effect and toxicity could occur in patients receiving sequential courses of cisplatin.

Effects of probenecid on enprofylline kinetics in man.

Enprofylline 1 mg/kg, a new potent antiasthmatic xanthine derivative, which is mainly eliminated by renal excretion, was given intravenously to 6 normal subjects with and without oral pretreatment with 1 g probenecid. The latter caused a drop in the average total body clearance of enprofylline from 21 to 9.8 l/h, and in the average renal clearance from 17 to 8.0 l/h. The average half-life increased from 1.8 to 3.0 h. The volumes of distribution, Vz and Vss, both fell by about 25%, indicating that probenecid had restricted the distribution of enprofylline in the body. The plasma protein binding of enprofylline was not altered by probenecid. The results confirm the opinion that active tubular secretion accounts for a large proportion of the total elimination of enprofylline.

Nonlinear renal clearance of ultrafilterable platinum in patients treated with cis-dichlorodiammineplatinum (II).

Nonlinear renal clearance of ultrafilterable platinum was observed in 5 of 7 patients given cis-dichlorodiammineplatinum (II) in doses of 50-140 mg/m2 by short-term infusion (2 h). Average renal clearance determined during and 24 h after infusion ranged from 100 to 543 ml/min and always exceeded creatinine clearance, suggesting that ultrafilterable platinum was renally secreted. Saturable tubular reabsorption was postulated on the basis that renal clearance was highest at peak plasma and urinary levels and fell as the levels declined. Although an overall relationship between dose and renal clearance was not apparent, one patient receiving the highest dose (140 mg/m2) had elevated average renal clearance (485 ml/min), probably associated with saturation of reabsorption, whereas a patient receiving 50 mg/m2 had the lowest average renal clearance (100 ml/min), indicating that either active secretion was lower, or tubular reabsorption was saturated. One patient also showed urine-flow-dependent changes in renal clearance. Four patients had transient rises in ultrafilterable platinum levels, which were attributed to changes in renal tubular reabsorption. The results suggest that renal clearance of ultrafilterable platinum is probably dependent on cis-DDP dose, urine flow rate, and individual variability in the extent of active secretion and tubular reabsorption. A sensitive HPLC method was applied and ultrafilterable platinum was detected in the plasma of all patients 24 h after infusion. Renal tubular reabsorption may result in prolonged plasma levels of ultrafilterable platinum, which could contribute to the drug's antitumour effect.

Pharmacokinetics of ceftriaxone in neonates and infants with meningitis

The pharmacokinetics of ceftriaxone was studied in the plasma, urine, and cerebrospinal fluid of seven neonates and seven infants with meningitis. In addition, plasma and urine data were obtained in five neonates and one infant receiving ceftriaxone for other serious infections. All neonates younger than 14 days received daily doses of 50 mg/kg ceftriaxone; all other patients but two received 100 mg/kg. The average weight-corrected values for total body clearance (ClT), volume of distribution (Vdss), and biologic half-life (t 1/2) were 0.37 ml/min/kg, 0.45 L/kg, and 16.2 hours in neonates younger than 1 week; 0.77 ml/min/kg, 0.48 L/kg, and 9.2 hours in neonates older than 1 week; and 1.03 ml/min/kg, 0.39 L/kg, and 7.1 hours in older infants, respectively. There was a significant difference in ClT and t 1/2 between the neonates younger and both neonates older than 1 week, and infants. The Vdss was not significantly different among the three age groups. The average renal clearance in neonates younger than 1 week (0.28 ml/min/kg was 70%, in neonates older than 1 week (0.54 ml/min/kg) was 77%, and in older infants (0.49 ml/min/kg) was 47% of ClT, indicating that nonrenal elimination was less developed in neonates. The quantitation of CSF diffusion of ceftriaxone was assessed by comparison of the areas under the CSF and plasma concentration-time curve. The mean ceftriaxone penetration into the CSF in neonates and infants with bacterial meningitis was 17%. On the other hand, penetration in patients with aseptic meningitis amounted to only 4%. Mean ceftriaxone concentrations in the CSF in patients with bacterial meningitis were 2.8 mg/L after 24 hours, exceeding by many times the minimum inhibitory concentration of the common meningitis pathogens at this time.

The pharmacokinetics of frusemide are influenced by age.

After a 24 h control period 80 mg frusemide was given intravenously over 2 min to a group of young and a group of elderly healthy male volunteers. The serum concentration of frusemide and the excretion in urine of the drug and a glucuronidated metabolite were followed for 24 h. The elimination of the drug from serum was described by an open two compartment model. The serum clearance (CLs) was 170 +/- 19 ml min-1 in the young and 129 +/- 11 ml min-1 in the elderly (P less than 0.01) and the average renal clearance (CLr) was 67% of CLs in the young and 58% of CLs in the elderly (NS). The average amount of unchanged frusemide in the urine during the first 30 min was 30 +/- 6 mg in the young but only 20 +/- 4 mg in the elderly (P less than 0.01). The albumin concentration in serum was 15% lower in the elderly but on the average the protein bound fraction of frusemide was 98.6% in both groups. The Vd ss did not differ between the two age groups (0.130 1 kg-1) but the elimination half-life was 70 +/- 20 min in the young and 102 +/- 33 min in the elderly (P less than 0.05). In the young 11.4 +/- 5.0 mg frusemide was excreted as a glucuronidated compound whereas this figure was only 5.4 +/- 2.9 mg in the elderly (P less than 0.01). It is concluded that the age-related changes in the fate of unchanged frusemide in the organism mainly can be explained by a reduction in the tubular secretion of the drug which in turn may be caused by a reduction in renal plasma flow.

Renal clearance of fluoride in a steady state condition in man: influence of urinary flow and pH changes by diet.

In order to study fluoride renal clearance, four subjects were given 3 mg fluoride as sodium fluoride tablets every 6 hrs for 60 hrs during two separate periods - during production of acid urine induced by a protein rich diet and during production of alkaline urine obtained by giving a vegetarian diet. Plasma and urine were collected every third hour for 72 hours during each experiment. In the protein rich diet period urinary pH was significantly lower than when the subjects were maintained on the vegetarian diet. Lower urinary output of fluoride during the protein rich diet experiment was recorded, however, the difference was not significant. Plasma fluoride at steady state was almost the same during both experiments. Renal fluoride clearance was significantly correlated to urinary pH in both types of experiments. When renal fluoride clearance was plotted versus urinary flow, the correlation was only significant during alkaline conditions. The average renal clearance was not significantly different between the two sets of experiments. It may be concluded, that pH and diuresis both influences fluoride renal clearance. Moreover, the results suggests that dietary components as such, influence renal clearance of fluoride in some way or another.

Clinical pharmacology of a new ureidopenicillin: Bay K 49999.

A new semisynthetic ureidopenicillin (Bay K 4999) demonstrates favorably in vitro antibacterial efficacy against human-pathogenic gram-negative rods in comparison to mezlocillin and azlocillin. A comparative paramcokinetic study was done with 10 test subjects after 30 min intravenous infusion of 4.0 g of Bay K and mezlocillin, respectively. The serum concentration course during a period of 10 h showed an open three-compartment model for both antibiotics. The urine recovery of Bay K 4999 during 24 h was only 32.6 +/- 4.3% of the applied dose. In three test subjects with normal renal function, the average renal clearance of Bay K was 61.0, the total serum clearance was 409.2 ml/min/1.73 m2. 31 patients were treated with a daily dose of 3 x 1.0--2.0 g Bay K for severe bronchopulmonary, UTI and cholangiogenic infections. The therapeutic results were good; the relatively high number of side effects should be further investigated in animal studies and require more clinical experience.

Effect of metabolic regulation on renal leakiness to dextran molecules in short-term insulin-dependent diabetics.

Renal clearance of dextran of two ranges of molecular size and glomerular filtration rate (GFR, 51Cr-EDTA) were measured in seven short-term insulin-dependent diabetics (mean age 25 years). Measurements were carried out in the same patient during good and poor metabolic regulation (plasma glucose, mean +/- SEM, 6.5 +/- 0.9 and 14.8 +/- 1.5 mmol/l, respectively). GFR was elevated in all patients during poor metabolic regulation (119 +/- 6 ml/min/1.73 m2, versus 99 +/- 2 ml/min/1.73 m2 during good control, p less than 0.01). The average renal clearance of dextran with molecular weights ranging from 25,000 to 35,000 and 35,000 to 45,000 increased during poor metabolic regulation from 14.8 +/- 0.8 to 19.8 +/- 1.8 ml/min/1.73 m2, and 5.2 +/- 0.3 to 6.8 +/- 0.6 ml/min/1.73 m2, respectively (p less than 0.05). The elevated GFR and renal dextran clearance found during poor metabolic regulation were normalized within one to three weeks of effective insulin treatment. This rapid reversibility can hardly be explained by the previously demonstrated enlargement in glomerular size and filtration surface area, since these alterations remain unchanged after more than one month of insulin treatment. The metabolic regulation did not influence the size-selective properties of the glomerular wall. Therefore, we suggest that the dominating mechanism involved in the GFR and renal dextran clearance alterations is functional, viz. increased filtration pressure.

Pharmacokinetics of bethanidine in hypertensive patients.

The pharmacolinetics of bethanidine-14C was studied in three hypertensive patients. A 25-MG DOSE OF BETHANIDINE-14 C hemisulfate was administered intravenously. Plasma levels of drug were measured over the first 6 hr. In 3 to 4 days, 89% to 94% of the dose was excreted in the urine. Thin-layer chromatography (TLC) and isotope dilution analysis of the urine samples indicated that only intact bethanidine was excreted. Plasma level and urinary excretion rate profiles had miltiphasic characteristics. Estimated half-lives of the terminal phase ranged from 7 to 11 hr. Average renal clearance over the initial 6 hr approached renal plasma flow. In 2 of the patients, renal clearance between 2 and 4 hr after administration was reduced to one-helf that observed during the initial 2-hr period. After single oral administration of a 25-mg dose of bethanidine-14C hemisulfate, 48% of 61% was excreted in urine and 15% to 48% in feces. Peak urinary excretion rates were reached 6 hr following administration. The urinary excretion kinetics of bethanidine during and after repetive oral dosing was also studied. A 25-mg dose was dividied into 12 to 16 equal doses and administered avery 6 hr. A larger fraction of the cumulative dose was recovered in the urine (72% to 74%) than after the single dose, suggesting higher availability at the lower dose. Steady-state urinary excretion rates were achieved in 4 to 7 doses. The steady-state urinary excretion levels were consistent with pharmacolinetic predictions based on single oral dose data. When 2 of the patients were given imipramine for 2 days prior to an oral 25-mg dose of bethanidine-14C hemisulfate, the terminal half-lives of the urinary excretion rate profiles were shorter than those in the same patients not given imipramine.

Doxycyclinum NFN: a pharmacological and bacteriological investigation.

In normal human subjects multiple dose trial with an initial dose of 400 mg doxycycline and subsequent doses of 200 mg every 24 hours gave average minimum serum concentrations of between 1 and 2 μg doxycycline/ml serum. The average urine concentrations varied between 100 and 200 μg doxycycline/ml urine, and 42 per cent of the drug administered was excreted in the urine in an active form. The average renal clearance of doxycycline determined over 96 hours was 28 ml/min. In a single dose trial with 200 mg doxycycline, an 8‐hour renal clearance of doxycycline was found to be 13 per cent of the creatinine clearance, and the serum half‐life period was found to be 11.6 hours. Microbiological assay was used for all determinations of doxycycline in the serum and urine. The in vitro sensitivity of 211 urinary tract pathogens to doxycycline and oxytetra‐cycline was investigated in order to determine the minimum inhibitory concentration (MIC). The strains, which originated from patients with chronic urinary tract infections, were as a whole only slightly sensitive to the two tetracyclines. Compared with oxytetracycline, doxycycline, assessed at the MIC‐level, showed a higher bacteriostatic effect in vitro, especially against gram‐positive strains.

STUDY OF PHENYLALANINE CLEARANCE IN THE PHENYLKETONURIC CHILD AND HETEROZYGOSITY TESTS IN AFFECTED FAMILIES

Summary1.The average renal clearance of phenylalanine in the Phenylketonurie child stands at a normal value : 0,84 ml/min/1,73 m2 of body surface. As in the normal subject the renal tubules of the phenylpyruvic idiot reabsorb most of the phenylalanine filtered at the glomeruli, though the glomerular filtrate is from 10 to 20 times richer in phenylalanine than the normal one.2.Upon 46 individuals taken among 3 affected families, the detection of the carrier state for phenylketonuria was carried out by means of the determination of the fasting phenylalanine plasma level. Good results were obtained in about 70 % of the cases. Other uncertain genotypes can however be ascertained with better accuracy by the oral load test with 1-phenylalanine; this was applied in a case of genetic advice.

Allantoin Clearance as a Measure of Glomerular Filtration Rate in Man.

ConclusionsThe average renal clearance of allantoin in 6 normal human subjects was found to be 123 cc per minute. The similarity of this value to that now accepted for the renal clearance of inulin...