Saturable Tubular Secretion Research Articles

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers.

Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination processes should be evaluated in more detail. Finafloxacin exhibited a favorable safety and tolerability profile. (This study has been registered at ClinicalTrials.gov under registration no. NCT01910883.).

Dose-Dependent Pharmacokinetics of Enprofylline and Its Renal Handling in Rats

The effect of dosage on the pharmacokinetics of the potent bronchodilator enprofylline (3-propylxanthine; PX) and its renal handling were investigated in rats. Enprofylline (PX) was administered iv in dosages of 2.5, 10, 20, and 40 mg/kg, and PX concentration in plasma and urine was determined by HPLC. The pharmacokinetic parameters were estimated by model-independent methods. The disappearance of PX from plasma was delayed as dosage was increased. The corresponding pharmacokinetic parameters also showed dose dependency; increases in the volume of distribution (Vd) and mean residence time (MRT) and a decrease in total body clearance (CLT) were observed as dosage was increased from 2.5 to 40 mg/kg. Approximately 80% of the dose, however, was excreted in urine as unchanged PX. Plasma protein binding studies of PX showed concentration dependency and allowed determination of binding parameters, with an apparent dissociation constant (Kd) of 162.50 μM and a binding capacity (nP) of 565.23 μM. Some pharmacokinetic parameters for unbound PX calculated by total plasma concentration and binding parameters also showed dose-dependent characteristics. However, no significant change in Vd for unbound PX was observed among administered doses, indicating that the distribution of PX into the body tissues is not changed by an increase in dosage. Renal clearance of unbound PX significantly increased as plasma concentration decreased. The maximum transport capacity (Vmax) and the Michaelis-Menten constant (Km) for tubular secretion were 60.53 μg/min and 2.27 μg/mL, respectively. The aim of the present study is to demonstrate that both saturable tubular secretion and concentration-dependent protein binding are responsible for the dose- dependent pharmacokinetics of PX in rats.

Pharmacokinetics and tolerance of romazarit after oral administration of ascending single doses to healthy human volunteers

Forty-four healthy male volunteers participated in an investigation of the pharmacokinetics and tolerance of single oral doses of romazarit, a potential disease-modifying antirheumatic drug. The study design involved single oral doses in ascending sequence from 40 to 1500 mg. At each dosage 9 volunteers were studied, of whom 6 received romazarit and 3 received placebo capsules in a double-blind manner. Tolerance was assessed before and after each of the 57 romazarit and 27 placebo doses. Plasma and urinary concentrations of romazarit were measured by HPLC with UV detection. Model-independent pharmacokinetic analyses showed that romazarit was rapidly and extensively absorbed in a dose-proportional manner. Urinary recovery of drug related material was about 70% of the dose and almost all in the form of labile metabolites (probably acyl glucuronides). Clearance was faster (greater than 3 l/h) at doses below 700 mg, than in the range 700-1500 mg (1.7 l/h). It is suggested that two or more clearance mechanisms are present. One of these mechanisms is saturable and may involve a reversible ester glucuronide formation coupled with saturable tubular secretion of glucuronides. Romazarit was well tolerated in these healthy volunteers. There were two reports of stomach pain, one associated with vomiting. Changes in laboratory safety test results and in measurements of vital signs were similar in frequency and magnitude after romazarit and after placebo doses.

Kinetic studies on drug disposition in rabbits. I. Renal excretion of iodopyracet and sulfamethizole.

In order to quantify the renal handling of iodopyracet (IOD) and sulfamethizole (SMZ), single-drug clearance studies in rabbits were performed under quasi-steady state conditions with stepwise increasing the infusion rate of IOD or SMZ. Although concentration dependence of plasma protein binding was observed for both drugs, the urinary excretion rate of IOD was proportional to its total plasma concentration at low total plasma concentrations of 0.05-0.8 mM. On the other hand, the relationship between urinary excretion rate and total plasma concentration of SMZ was a concave-ascending curve at low plasma concentrations and the renal clearance of SMZ was sensitive to changes in plasma protein binding. However, renal clearances referenced to unbound plasma concentration at total plasma concentrations of 0.05 mM for IOD and SMZ were 9.5 and 38 l/h, respectively. Those values were much greater than the effective plasma flow in rabbits. These facts indicated that the intrinsic clearances at the sites of tubular secretion were high and that the rates of secretion were fully or partially limited by the renal plasma flow. Furthermore it was suggested that unbound drug was liberated from plasma protein at the sites of tubular secretion. The data obtained at high plasma concentrations indicated that the tubular secretion of IOD had capacity limited characteristics and that the urinary excretion of SMZ involved tubular reabsorption as well as saturable tubular secretion. From the data obtained, a perfusion-limited pharmacokinetic model was constructed characterizing the excretory processes, namely, glomerular filtration, passive tubular reabsorption, saturable tubular secretion and reequilibrium between bound and unbound drugs in plasma. For both drugs, the estimates for bulk flow rate were reasonable values of effective renal plasma flow and the dissociation constants for tubular secretion agreed well with those for in vitro renal cortex accumulation, suggesting that the kinetic model based on physiological concepts was useful for the understanding of the drug elimination processes.