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.

Pharmacokinetic characteristics of N7-substituted theophylline derivatives and their interaction with quinolone in rats.

Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CLT) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 L/h/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal clearance (CLR) was 1.75 L/h/kg, approximately 13-fold the CLR for PXP (0.13 L/h/kg) and sevenfold the rat glomerular filtration rate. This study indicates that in rats, DPP is mainly excreted by active tubular secretion and that renal tubular reabsorption contributes to renal excretion of PXP with glomerular filtration. No significant changes in any pharmacokinetic parameters of the two drugs were observed when they were coadministered with enoxacin, compared with the drug administered alone, suggesting that enoxacin had no effect on the pharmacokinetics of either drug.

Structure-related inhibitory effect of quinolones on alkyl-xanthine elimination in rats.

To investigate the relationship between the chemical structures of quinolones, enoxacin (ENX) and its analogues, and their metabolic inhibitory effects on theophylline, a xanthine derivative closely related to theophylline, 1-methyl-3-propylxanthine (MPX), was used as a model of theophylline in rats. The disappearance of MPX from plasma was significantly delayed by treatment with ENX and analogue A (derivatives without substituent group at both 3'- and 5'- carbon atom in the piperazinyl ring): total body clearance of MPX was significantly decreased by approximately 50%. However, analogue A was converted into ENX in the rat body (about 14% of dose). Analogues B and C (derivatives with substituent group at 3'- or 5'-carbon atom in the piperazinyl ring) had little or no effect on MPX disposition. No significant change in the volume of distribution of MPX was observed after coadministration with these quinolones. The results of this study indicate that the substitutions on 3' and 5'-carbon atoms of piperazinyl ring at 7-position of the quinolone molecule may play important role in the inhibition of theophylline metabolism.

Structure-pharmacokinetic relationships among the N1,N3-alkylxanthines in rats.

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1,N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P less than 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.

The possible mechanism of interaction between xanthines and quinolone.

To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4-oxo-enoxacin, on the disposition of new xanthine derivatives, 1-methyl-3-propylxanthine (MPX) and 3-propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg-1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4-Oxo-enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY-198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4-oxo-enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N-demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines.

Effect of mequitazine on the pharmacokinetics of theophylline in asthmatic patients.

The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200-400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.

Correlation between hydrophobicity of N-alkylxanthine derivatives and their biological activities on guinea-pig isolated tracheal smooth muscle.

Cyclic (c) AMP phosphodiesterase (PDE) inhibitory activities of N-alkylxanthine derivatives (3-methyl-,3-ethyl-,3-propyl-,3-butyl-,1,3-dimethyl-,1-methyl-3-ethyl-,1-methyl - 3-propyl- and 1-methyl-3-butyl xanthines) and their relaxant effects on carbachol-induced contraction and on resting tone guinea-pig isolated tracheal smooth muscle have been investigated. The PDE inhibition constant (Ki) and the concentration producing 50% tracheal smooth muscle relaxation in-vitro (EC50) were determined. Significant correlations between the -log Ki values and the -log EC50 values on the carbachol-induced contraction or on the resting tone were found (r = 0.902 and 0.892). The apparent partition coefficient (P) between n-octanol and pH 7.4 phosphate-buffered saline (PBS) was measured as an index of hydrophobicity of the xanthine derivatives. There were significant correlations between log P and both -log EC50 values and between the log P and -log Ki values. These findings suggest that the cAMP PDE inhibitory activity of N-alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.

Kinetic interaction between theophylline and a newly developed quinolone, NY-198.

The effect of a newly developed quinolone, NY-198, on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in six male healthy volunteers, in a crossover fashion. A sustained-release theophylline formulation (200 mg twice daily at 12 h intervals) was received as monotherapy or coadministration with NY-198 (200 mg twice daily at 12 h intervals). No significant change in the pharmacokinetic parameters of theophylline was observed during coadministration of NY-198. No significant change in urinary excretion of theophylline and its metabolites was also observed. These findings indicate that NY-198 does not influence the pharmacokinetics of theophylline and we can suggest that quinoline derivatives have less effect on theophylline disposition than 1,8-naphthyridine derivatives among quinolones.

Protein binding characteristics of a new bronchodilator, 1-methyl-3-propylxanthine (MPX), in different species.

The protein binding of a new bronchodilator, 1-methyl-3-propylxanthine (MPX), in different animal species sera (human, dog, rabbit, rat and mouse) was investigated in vitro by ultrafiltration method. Interspecies differences in the binding affinity and binding capacity for MPX were observed. The dissociation constant (Kd1) for the high affinity binding site of human serum was approximately 17 times higher than that of rat serum. Those of rat serum and rabbit serum were nearly equal. On the other hand, the binding indices (n1p1/kd1) of human serum and rat serum were comparable. The binding of MPX to various proteins such as human serum albumin (HSA), alpha 1-acid glycoprotein (AGP) and isolated human lipoproteins was also investigated. The binding of MPX to HSA was lower than that of human serum protein but the number of specific binding sites (n1) in human serum was in agreement with that in HSA. The binding curves of MPX to AGP and lipoproteins were almost linear and the binding percentages were less than 7% in both cases. These data suggest that MPX is exclusively bound to albumin and that AGP and lipoproteins are of little importance in the protein binding of MPX. The present data appear to be useful for predicting the role of protein binding on the pharmacokinetics of MPX in different animal species.

Lack of effect of repirinast on the pharmacokinetics of theophylline in asthmatic patients.

A possible pharmacokinetic interaction between theophylline and repirinast has been investigated in asthmatic patients. The kinetics of theophylline was studied in seven adult in-patients given theophylline 400-800 mg b.d. alone and after three weeks of co-administration of repirinast. There was no effect on the kinetics of the combined treatment.