Pharmacokinetic/pharmacodynamic modelling of roxithromycin for the inhibitory effect of tumour necrosis factor-alpha and interleukin-6 production in dogs.
The objective of the present study was to determine and characterize the relationship between the plasma concentration of roxithromycin, and its inhibitory effect on cytokine production, in order to predict its possible clinical relevance. Six healthy beagle dogs received a single intravenous dose of 20-mg roxithromycin per kg body weight. Blood samples were obtained at different time points. The plasma was analysed with respect to roxithromycin, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The concentration-effect relationship was explored by modelling the data using two compartmental model and an indirect response model with an E(max) concentration-effect relationship. The estimated pharmacokinetic parameters (geometric mean) were as follows: V(c) = 2.59 l; k(10) = 0.08/h; k(12) = 0.26/h; k(21) = 0.40/h. The pharmacodynamic parameters (geometric mean) for the inhibitory effect on cytokine production induced by heat-killed Staphylococcus aureus (HKSA) were for TNF-alpha (k(in) = 1.42 microg/h; k(out) = 1.10 microg/h; EC(50) > 5.69 mg/l) and for IL-6 (k(in) = 2.31 microg/h; k(out) = 2.04 microg/h; EC(50) = 21.07 mg/l) production, respectively. The inhibitory effect of roxithromycin on production can be adequately described by the indirect response model with an E(max) concentration-effect relationship.
Lim
J-H
JH
College of Veterinary Medicine, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon, Korea.
Park
B-K
BK
Yun
H-I
HI
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004285:Dogs / Q000097:blood*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D011897:Random Allocation; D015575:Roxithromycin / Q000493:pharmacokinetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D000900:Anti-Bacterial Agents; D015850:Interleukin-6; D015575:Roxithromycin; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors