Pharmacokinetic evaluation of high pulmonary disposition of clarithromycin after systemic administration.
1. The distribution characteristics of clarithromycin to the lung were investigated in vivo and in isolated lung perfusion experiments. The in-vivo integration plot analysis showed that the pulmonary uptake and extracellular distribution in the lung were significantly higher for clarithromycin than for erythromycin. 2. In the rat lung single-pass perfusion study, the pulmonary extraction ratio (E(ss)) of clarithromycin at steady-state was significantly higher than that of erythromycin, and the E(ss) of clarithromycin tended to decrease as the inflow concentration increased, suggesting the involvement of carrier-mediated transport in the pulmonary disposition of clarithromycin. 3. The outflow patterns of clarithromycin or erythromycin at various inflow concentrations were simultaneously analysed based on a pharmacokinetic model, which consists of the non-specific binding site, the specific binding site and the subsequent uptake process. The parameters obtained suggested that clarithromycin would have the higher affinity and higher capacity for the specific binding site, and the higher equilibrium constant for the non-specific binding site than erythromycin. 4. The simulation study using those parameters demonstrated that clarithromycin could be bound to the specific binding site and subsequently taken up more extensively than erythromycin. 5. A multiple-indicator dilution study also indicated that clarithromycin was more readily associated and extracted with the lung than with erythromycin. In the inhibition study, it was suggested that the pulmonary uptake of clarithromycin could be ascribed not only to the non-specific binding depending on its lipophilic nature, but also in part to some specialized mechanisms such as organic cation transporters.
Kubo
J-I
JI
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Ohigashi
Y
Y
Hamabe
M
M
Ogawara
K-I
KI
Higaki
K
K
Saito
H
H
Kimura
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001665:Binding Sites; D002412:Cations; D017291:Clarithromycin / Q000493:pharmacokinetics*; D004917:Erythromycin / Q000493:pharmacokinetics; D007700:Kinetics; D008168:Lung / Q000187:drug effects*; D008297:Male; D008956:Models, Chemical; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000900:Anti-Bacterial Agents; D002412:Cations; D004917:Erythromycin; D017291:Clarithromycin