Pharmacokinetics of theophylline and enprofylline in patients requiring a high or low dose of theophylline

Summary In patients requiring a high or low dose of theophylline the pharmacokinetics of theophylline and enprofylline were studied. The low-dose group took an average daily dose of 8.91 mg/kg body wt. and the high-dose group 24.75 mg/kg body wt. The average half-life of theophylline in the former was 7.11 h and in the latter 4.72 h. The average clearances (CL) of theophylline were 2.83 and 4.58 l/h, respectively. The daily oral intake of theophylline was negatively correlated with the theophylline t_1/2 (r=–0.63). While the t_1/2 of enprofylline was similar in the two groups, CL and volume of distribution (V_c) were slightly (about 30%) but significantly higher in patients requiring a high dose of theophylline. CL of enprofylline did not correlate with CL of theophylline, nor was the V_c of the two drugs correlated. Interindividual variability in t_1/2 and CL was considerably lower for enprofylline than for theophylline.     

Alterations in Renal Uptake Kinetics of the Xanthine Derivative Enprofylline in Endotoxaemic Mice

The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg^?1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (V_max) from 17.3 to 32.2 μg h^?1 g^?1 of kidney and in the Michaelis–-Menten constant (K_m) from 2.7 to 21.7 μg mL^?1 and decrease in the nonsaturable uptake rate constant (K_d) from 0.87 to 0.43 mL h^?1 g^?1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.     

Enprofylline pharmacokinetics in children with asthma

Summary The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma.The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a noninvasive method to study the elimination rate.As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, V_z, averaged 0.58 l/kg.Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m² body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight.Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.     

Influence of Age on the Disposition and Renal Handling of Enprofylline in Rats

Abstract— The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (V_max) (223·33,160·24 and 142·98 μg min^?1 kg^?1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (V_max/K_m) of enprofylline (75·45, 51·03 and 44·13 mL min^?1 kg^?1, respectively), while a slight change in the Michaelis-Menten constant (K_m) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.     

Capacity-limited renal glucuronidation of probenecid by humans

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet _1/2 increased from 3 to 6 h. TheC _max was 14μg/ml with a dosage of 250 mg, 31μg/ml with 500 mg, 70μg/ml with 1,000 mg and 120μg/ml with 1,500 mg. Thet _max remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6–0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34–59%). The protein binding of probenecid glucuronidein vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate-time profile of probenecid glucuronide shows a plateau value of approximately 700μg/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects itsV _max of formation.     

Pharmacokinetics of enprofylline in patients with impaired renal function after a single intravenous dose

Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, V and V_ss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.     

Effect of probenecid on the elimination and protein binding of ceftriaxone

Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d.Probenecid increased the total systemic clearance (CL _S ^T ) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t _1/2() ^T ) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL _R ^F ) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone.The final value of CL _R ^F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL _NR ^F ) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL _S ^F ) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg).As a consequence of a decreased affinity constant (K_A), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid.The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.Abbreviations AUC^T, AUC^F plasma AUC of total and free (unbound) drug - CL _S ^T , CL _S ^F clearance: total systemic, free systemic - CL _O ^T , CL _R ^F total oral, free renal - CL _NR ^F free non-renal - V _Z ^T V _SS ^T apparent volume of distribution: terminal phase, total drug; corrected steady-state, total drug [14] - f average free fraction of drug in plasma - f_e fraction of dose excreted unchanged in urine - t _1/2() ^T terminal t_1/2: total drug - t _1/2() ^F free drug - K_A affinity constant - nP capacity constant - C _av ^ss steady-state concentration in plasma during multiple dosing - C_B bound concentration - C_F free (unbound) concentration     

Enprofylline: Pharmacokinetics and comparison with theophylline of acute effects on bronchial reactivity in normal subjects

Summary In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml · kg^–1 · h^–1, volume of distribution 0.48 l · kg^–1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV_1.0 (PC₂₀). Mean PC₂₀ values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC₂₀ ^Safter placebo and theophylline was statistically significant (p<0.05). At the time of determination of the PC₂₀, the serum concentration of enprofylline was between 16.5 and 11.8 µmol/l, and that of theophylline was between 78.3 and 61.1 µmol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.In fulfillment of his thesis (Dr. med.)     

Saturable kinetics of intravenous chlorothiazide in the rhesus monkey

A range of bolus doses of ¹⁴ C-chlorothiazide and unlabeled drug (6.7–30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g chlorothiazide per kg body weight basis. Clearances in the presence of probenecid decreased two-to four-fold over those seen without probenecid. Incremental renal clearances of chlorothiazide in the studies with and without probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants V_max and K_m were calculated for renal excretion of chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to chlorothiazide renal clearance was found to be negligible. Values of the constant K_I (the concentration of the probenecid competitive inhibitor of chlorothiazide, which doubles the apparent K_m value of chlorothiazide) were calculated using the previously calculated V_max and K_m values.Supported in part by NIH grants GM 26691 and AM 20884. During the course of this work, Dr. Gustafson received support as an NIH Predoctoral Fellow (GM 00752) and as a Fellow of the American Foundation for Pharmaceutical Education.     

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

AIMS

Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites.

METHODS

A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532–41). Subjects received 200 mg ciprofloxacin as 30-min intravenous infusion without and with 3 g probenecid divided into five oral doses. Drug concentrations were analysed by liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography. Ciprofloxacin and its 2-aminoethylamino-metabolite (M1) in plasma and urine with and without probenecid were modelled simultaneously with WinNonlin®.

RESULTS

Data are ratio of geometric means (90% confidence intervals). Addition of probenecid reduced the median renal clearance from 23.8 to 8.25 l h⁻¹[65% reduction (59, 71), P < 0.01] for ciprofloxacin and from 20.5 to 8.26 l h⁻¹ (66% reduction (57, 73), P < 0.01] for M1 (estimated by modelling). Probenecid reduced ciprofloxacin nonrenal clearance by 8% (1, 14) (P < 0.08). Pharmacokinetic modelling indicated competitive inhibition of the renal tubular secretion of ciprofloxacin and M1 by probenecid. The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 than for probenecid, based on the molar ratio. Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin.

CONCLUSIONS

Probenecid inhibited the renal tubular secretion of ciprofloxacin and M1, probably by a competitive mechanism and due to reaching >100-fold higher plasma concentrations. Formation of M1, nonrenal clearance and distribution of ciprofloxacin were not affected.     

Dosage adjustment for ceftazidime in patients with impaired renal function

Summary Ceftazidime has good antibacterial activity against many Gram-negative micro-organisms including Ps. aeruginosa.The aim of the present study was to calculate a dosage adjustment regimen for renal failure patients and to test it in a second group of patients. A study was made of the pharmacokinetics of ceftazidime 1 g given as a single bolus i.v. injection in 20 patients in an intensive care unit with varying degrees of renal function, including patients on regular haemodialysis. The serum half-life of elimination (t_1/2) varied from 1.6 to 45 h depending on renal function. During haemodialysis the mean t_1/2 was 4.7 h. A good correlation between the renal clearance of creatinine and ceftazidime was observed. In most patients protein binding was lower than previously observed. From the pharmacokinetic data, a dosage adjustment regimen for patients with renal insufficiency was calculated, which studies in 7 further patients showed to be effective.Abbreviations C_t serum concentration at time t - and slopes of the bi-exponential curve of the fast and the slow disposition (overall elimination) processes - A and B intercepts of the distribution slope and elimination slope extrapolated to the ordinate - t_1/2 serum half-life of elimination - k₁₂ distribution rate constant for transfer from the central to the peripheral compartment - k₂₁ distribution rate constant for transfer from the peripheral to the central compartment - k₁₃ elimination rate constant from the central compartment - k_N and elimination rate constants from the central compartment in normal and impaired renal function, respectively - AUC area under the serum concentration-time curve from zero to infinity - V_t total apparent volume of distribution (area method) - V₁ and V₂ distribution volumes in the central and the peripheral compartments, respectively - CL total body clearance of ceftazidime - CL_R renal clearance of ceftazidime - CL_CR renal clearance of creatinine - T and dosing intervals in normal and impaired renal function - (m) pe (mean) prediction error - rmspe root mean squared prediction error     

Pharmacokinetics of enprofylline in healthy elderly subjects

Summary The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion.As expected the mean creatinine clearance (92.5 ml·min^–1· 1.73 m^–2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 1·h^–1·kg^–1 and the renal clearance was 0.13 l·h^–1·kg^–1, which was significantly lower than that in the young controls (0.28 and 0.22 l·h^–1·kg^–1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h).It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.     

Interspecies differences and scaling for the pharmacokinetics of xanthine derivatives.

Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1-methyl-3-propylxanthine (MPX), were investigated in mice, rats, guinea-pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model-independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non-renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals.     

Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit

The effect of probenecid on the renal excretion of zidovudine (3'-azido-3'-deoxythymidine; AZT) and its distribution into CSF was studied in the rabbit. Although probenecid is chemically unrelated to AZT, it has been shown that probenecid inhibits AZT elimination in Acquired Immunodeficiency Syndrome (AIDS) patients. The effect of probenecid on the renal clearance of AZT after an iv bolus dose was studied in crossover experiments in the absence (control) and the presence of a continuous iv infusion of probenecid. Probenecid coadministration increased the AZT plasma AUC by 70%, by proportionally decreasing the total body clearance. The renal clearance decreased by 50%. The effect of probenecid on the renal clearance of AZT at steady state was studied by measuring the renal clearance of AZT at different steady-state plasma probenecid concentrations. The renal clearance of AZT decreased with increasing probenecid concentration, suggesting competitive inhibition of the secretion of AZT in the renal tubule. The relationship between AZT renal clearance and probenecid plasma concentrations, during and after probenecid iv infusion in conscious and in anesthetized uretercannulated rabbits, showed hysteresis, indicating that probenecid plasma concentration is different from the concentration at the site of interaction. This suggests the presence of an effect compartment for the inhibition of AZT renal excretion by probenecid. The effect of probenecid on the CSF distribution of AZT was also studied in the rabbit. Probenecid coadministration caused a sevenfold increase in the AZT AUCCSF in probenecid-treated rabbits when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Capacity-limited renal glucuronidation of probenecid by humans A pilotVmax-finding study

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet _1/2 increased from 3 to 6 h. TheC _max was 14g/ml with a dosage of 250 mg, 31g/ml with 500 mg, 70g/ml with 1,000 mg and 120g/ml with 1,500 mg. Thet _max remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6–0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34–59%). The protein binding of probenecid glucuronidein vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate-time profile of probenecid glucuronide shows a plateau value of approximately 700g/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects itsV _max of formation.     

Effect of cirrhosis and renal failure on the kinetics of clotiazepam

Summary The kinetics of a single 5-mg oral dose of the thienodiazepine clotiazepam was evaluated in a series of patients with biopsy-proven cirrhosis, and in patients with renal insufficiency requiring maintenance hemodialysis, compared to healthy matched controls. Clotiazepam volume of distribution (V_z) was significantly smaller in cirrhotic patients than in controls (1.83 vs 2.57 l/kg), and total clearance was likewise reduced (2.15 vs 3.15 ml/min/kg). Elimination half-life was similar between groups (10.0 vs. 10.2h). There were no significant differences between renal failure and control patients in clotiazepam V_z, oral clearance, or elimination half-life. Thus cirrhosis is associated with reduced clearance of clotiazepam, probably due to impairment of its microsomal oxidation. However clotiazepam disposition is not significantly altered in dialysis-dependent renal insufficiency patients.Supported in part by Grant OC 10/6–4 from Deutsche Forschungsgemeinschaft, and Grant MH-34223 from the United States Public Health Service.     

Additive bronchodilator effects of terbutaline and enprofylline in asthma

Summary Enprofylline is a novel xanthine derivative with negligible adenosine antagonizing ability. It is eliminated almost exclusively by renal clearance with a half-life of about 2 h. Three i.v. infusions of enprofylline (1 mg/kg body weight over 10 min) were given at hourly intervals to 16 patients with stable, reversible airway obstruction. The patients were pretreated at random with i.v. terbutaline (4 µg/kg body weight) or placebo according to a double blind cross-over design. Lung function and drug concentrations in plasma were followed. Enprofylline produced significant and concentration-dependent bronchodilatation between plasma levels of 1.24 and 3.22 mg/l. The improvement in ventilatory function was significantly enhanced by terbutaline pretreatment. At the highest plasma levels of enprofylline nausea and headache were found as subjective side effects. The results suggest that enprofylline and terbutaline might best be used in a low dose combination in the treatment of bronchial asthma.     

An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-type hypersensitivity

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR−) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower (P < 0.05) in probenecid TR− rats (0.03 ± 0.02 l/h) than in normal control (0.09 ± 0.05 l/h), in normal probenecid (0.10 ± 0.07 l/h) and in TR− control rats (0.13 ± 0.07 l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.     

The Effects of N-Benzoyl-β-alanine,a New Nephroprotective Drug,on the Distribution and Renal Excretion of Enprofylline in Rats

Abstract— The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg^?1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL^?1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL^?1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL^?1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline.

The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose-independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single-injection renal clearance method, were 21.25 micrograms/mL for the Michaelis-Menten constant and 102.38 micrograms/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady-state volume of distribution of DPP. The effect of probenecid concentration on the steady-state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid-insensitive transport systems for DPP in the renal proximal tubule. The Michaelis-Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 micrograms/mL.