Toxicokinetic approach for evaluating respiratory depression effect of aminoglycoside antibiotics: species differences in drug susceptibility.
The respiratory depression effect of aminoglycoside antibiotics was studied by a toxicokinetic approach, and species differences in drug susceptibility were elucidated based on plasma concentrations. An allometric relationship was obtained between total body clearance of arbekacin, a novel aminoglycoside antibiotic, and animal body weight. The power was 0.714, less than unity, which means smaller animals have higher ability to eliminate the drug from the body and need higher doses to attain a certain steady-state plasma concentration. When the infusion rate of arbekacin was altered, the total dose required to cause the toxicologic endpoint for respiratory depression (60 per cent loss of respiratory rates) changed greatly, but the plasma concentration of arbekacin at the toxicologic endpoint remained at almost a constant level. The concentration at the toxicologic endpoint was similar for all of the animal species examined and was 650-950 micrograms ml-1, even though the total dose required to cause the toxicologic endpoint varied greatly among the animal species. These findings suggest that the toxicologic effect compartment for respiratory depression is indistinguishable from the plasma compartment, and that species differences in the total dose are due to differences in pharmacokinetics of the drug, mainly in the total body clearance, but not to differences in intrinsic susceptibility to the drug.
Komiya
I
I
Pharmaceutical Research Center,Meiji Seika Kaisha, Ltd, Yokohama, Japan.
Mitomi
N
N
Kuribayashi
T
T
Takata
H
H
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D003982:Dibekacin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000139:chemically induced*; D013045:Species Specificity
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D003982:Dibekacin; C031986:arbekacin