Clinical pharmacology of antimicrobial pylidonecarboxylic acids (III) ‒Comparative study of newly developed compounds on pharmacokinetics in healthy humans‒

We compared the pharmacokinetics of 8 newly developed antimicrobial quinolones with those of ciprofloxacin (CPFX). ofloxacin (OFLX) and sparfloxacin (SPFX) in healthy human. Based on the average time course of serum concentrations after a single oral dose of each drug (normalized to 200 mg). grepafloxacin (GPFX) and NM 441 were similar to SPFX with low C_max. and long t_1/2; temafloxacin (TMFX), balofloxacin (BLFX), AM-1155 and DU-6859 a were similar to OFLX with high C_max and large AUC; Y-26611 was similar to CPFX with low C_max, and short t_1/2 and small AUC; pazufloxacin (PZFX) was a new type with high C_max, and short t_1/2. However, in the cumulative urinary recovery of the unchanged drug. TMFX, BLFX, PZFX, AM-1155 and DU- 6859 a as well as OFLX; had high values Y-26611 and NM 441 had lower values than CPFX; and GPFX and SPFX had the lowest values. We also tried design an optimum dosing regimen on the basis of the serum AUC/MIC, a possibly important factor in the therapeutic efficacy of this type of drug. GPFX and NM 441 as well as SPFX might require less frequent but NM 441 might require a higher dose than SPFX. TMFX, BLFX and AM-1155 might have stronger effects than OFLX especially against Streptococcus pneumoniae. It is suggested that DU-6859 a does not need as high a dose but Y-26611 requires a higher dose than OFLX and CPFX. The therapeutic effect of PZFX might be similar to that of CPFX, but an advantage of its high C_max in the therapeutic effect remains to be shown. The pharmacokinetic relationships of 16 antimicrobial quinolones including 9 previously reported derivatives in healthy humans and in five laboratory animal species were investigated according to Boxembaum's approach. All the parameters of apparent plasma clearance, renal clearance and apparent steady state volume of distribution in humans had the best correlation with those in rabbits among mice, rats, rabbits, dogs and monkeys. However, the t_1/2 in humans was significantly correlated with that only in dogs, though the correlation coefficiency was low (r=0.617). These results support the idea that the overall pharmacokinetic behavior of an antimicrobial quinolone in humans can be estimated with sufficient accuracy from that obtained in preclinical studies.