Pharmacokinetics and penetration into tissue fluid of ceftizoxime in normal and hyperthermic sheep

The pharmacokinetics of ceftizoxime was studied in six sheep before and aft er inducing hyperthermia using Escherichia coli endotoxin, Sheep implanted subcutaneously with cages of non-reactive material for collecting tissue ca ge fluid (TCF) were used to conduct two trials. In Trial 1 animals with nor mal basal temperature (normal sheep (NS)) were given intravenous (i.v.) and intramuscular (i.m.) monodoses of ceftizoxime (20 mg/kg BW) at 1 week inte rval. One and 5 weeks later (Trial 2) each sheep were injected 1 mu g/kg BW of endotoxin to produce hyperthermia (hyperthermic sheep (HS)) previously to i.v. administration (HSi.v.) and i.m. (HSi.m.) of ceftizoxime (20 mg/kg BW), respectively. Serum and TCF samples were collected over 6 h post-admin istration. Ceftizoxime concentrations in serum and TCF were determined by a microbiological assay. The concentrations in serum and TCF of ceftizoxime were analyzed through compartmental and non-compartmental models. Rectal te mperature were significantly incremented in all animals during Trial 2. The half-time and constant of elimination in serum of ceftizoxime in NSi.v. (t (1/2) = 1.1 +/- 0.4 h; lambda(2) = 0.7 +/- 0.2 h(-1)) were statistically di fferent those observed in HSi.v. (t(1/2) = 1.4 +/- 0.4 h; lambda(z), = 0.5 +/- 0.2 h(-1)). The constants of distribution in NSi.v. and HSIV were 5.1 /- 4.6 and 3.1 +/- 3.4 h(-1) respectively. The time to reach the maximum co ncentrations in TCF was latter (p < 0.05) in NS (t(max) = 2.3 +/- 0.7 h) th an in HS (t(max) = 1.3 +/- 0.6 h). After i.m. administration in NS the abso rption half-life (0.12 +/- 0.19 h) was latter (p < 0.05) than in HS (0.06 /- 0.007 h) with greater areas under the curve (AUC in NS = 65.4 +/- 20.8 a nd AUC in HS = 34.7 +/- 7.5 (mu g/ml) h). The maximum value of concentratio n in serum (C-max) and AUC in TCF were greater (p < 0.05) in NS (C-max = 46 .1 +/- 10.6 mu g/ml and AUC = 84.3 +/- 17.3 (mu g/ml) h) as compared to sam e HS (C-max = 27.0 +/- 12.9 mu g/ml and AUC = 47.9 +/- 3.9 (mu g/ml) h). Th e concentrations of ceftizoxime in TCF after i.v. and i.m, in NS and HS wer e elevated during a 6 h period after administration. The bioavailability of ceftizoxime in NS (101.6 +/- 59.9%) and HS (87.4 +/- 63.3%) was suitable f or its use by the i.m. route. (C) 2000 Elsevier Science B.V. All rights res erved.