Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids

E. Okezaki, T. Terasaki, M. Nakamura, O. Nagata, H. Kato, A. Tsuji

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Comparative physiological pharmacokinetic analysis has been carried out to elucidate the different tissue distribution characteristics among eight pyridonecarboxylic acids including newly developed NY-198. The urinary and fecal recoveries of NY-198 were 76.3 ± 1.3% and 21.0 ± 0.1% of the does (mean ± SE, N = 3), respectively, after the iv administration of [14C]NY-198 as a 20 mg/kg dose. Model-independent moment analysis of the serum concentration-time profile of [14C]NY-198 gave the volume of distribution at steady state per body weight (V(dss)/BW) as 1150 ml/kg. Intrinsic renal clearance (CL (int, kd)) and intrinsic hepatic clearance (CL(int,lv)) were estimated to be 7.68 ml/min/kg and 6.33 ml/min/kg, respectively, by the cumulative urinary recovery and the area under the curve of the serum concentration-time profile of NY-198 and the blood flow rate. The tissue-to-serum partition coefficients (K(p)) were determined from the analysis of the tissue and serum concentration-time profiles after iv bolus or infusion of nalidixic acid, NY-198, and its structural analogue NY-239. These values were also determined from the analysis of similar data reported in the literature for the other pyridonecarboxylic acids (enoxacin, miloxacin, ofloxacin, pefloxacin, and pipemidic acid). The K(p) values of NY-198 ranged from 0.22 to 4.85 and were very similar to those for ofloxacin, being the highest in the disposing organs, kidneys and liver, the lowest in fat and brain, and modest in the other nondisposing organs. A good correlation (r = 0,981) was obtained between serum unbound fraction (f(p)) and the steady state distribution volume per body weight (V(d(ss))/BW), which was determined from the tissue partition coefficient. Additionally, comparatively good correlations were also obtained between f(p) and K(p) or apparent tissue-to-serum concentration ratio (K(p,app)). Thus, the difference of serum unbound fraction has been demonstrated for the determining factor of the structure-dependent tissue distribution difference, whereas the tissue binding has been suggested to be only slightly different for respective tissues among PCA derivatives. The concentration-time profile for serum and tissues (lung, heart, muscle, kidney, liver, spleen, gut, bone, skin, and brain) was predicted for NY-198 by physiological pharmacokinetics using the averaged tissue-to-serum unbound concentration ratio (K(p,f)), which was determined from the K(p,f) of eight PCA analogues. A fairly good coincidence was obtained between predicted and observed values of serum and tissue concentrations, indicating that the averaged K(p,f) value is a useful parameter for the reliable prediction of tissue distribution for the analogues of PCAs.

Original languageEnglish
Pages (from-to)865-874
Number of pages10
JournalDrug Metabolism and Disposition
Issue number6
Publication statusPublished - 1988
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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