Transport of Azithromycin into Extravascular Space in Rats.
Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent protein-unbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
Shinji
S
Kobuchi
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
Miki
M
Aoki
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
Chiaki
C
Inoue
Center for Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Hiroyuki
H
Murakami
School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan.
Akiko
A
Kuwahara
Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan.
Tsutomu
T
Nakamura
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan.
Hiroyuki
H
Yasui
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
Yukako
Y
Ito
BioSerenTach Inc., Kyoto, Japan.
Kanji
K
Takada
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan sakaedat@mb.kyoto-phu.ac.jp.
Toshiyuki
T
Sakaeda
D061605:Administration, Intravenous; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D017963:Azithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D016903:Drug Monitoring / Q000295:instrumentation / Q000379:methods; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009339:Needles; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D017963:Azithromycin