FACTORS AFFECTING THE PHARMACOKINETICS OF PARENTERAL CHLORAMPHENICOL IN ENTERIC FEVER

Chloramphenicol pharmacokinetics were studied in 29 Nepalese adults di agnosed with uncomplicated enteric fever and randomized to receive suc cinate ester 30 mg/kg iv or im. Serial plasma concentrations of chlora mphenicol, and iothalamate (to estimate glomerular filtration rate), a ntipyrine (hepatocellular function) and Indocyanine Green (liver blood flow) were measured by HPLC and kinetic parameters estimated by non-c ompartmental analysis. In culture-positive patients (n = 16), mean res idence times (MRTs) and steady-state volumes of distribution (V(d)ss) for iv chloramphenicol (mean +/- S.D.; 4.9 +/- 0.9 h and 1.9 +/- 0.8 L /kg; n = 7) were less than after im chloramphenicol (12.3 +/- 7.3 h an d 3.7 +/- 2.5 L/kg; n = 9; P < 0.05), with a higher peak plasma concen tration after iv (16.2 +/- 9.1 versus 7.8 +/- 3.6 mg/L; P < 0.05); pla sma clearance (Cl-p) was similar in the two groups (368 +/- 172 and 31 0 +/- 224 mL/kg/min after iv and im respectively). In 17 patients exam ined during convalescence, MRT and V(d)ss were less than in acute illn ess regardless of route chloramphenicol administration. There were sim ilar changes in chloramphenicol kinetic parameters in culture-negative patients. Antipyrine Cl-p and liver blood flow correlated weakly with chloramphenicol Cl-p in culture-positive patients (P less than or equ al to 0.1) and were higher in convalescence; no such associations were seen for iothalamate Cl-p. These data indicate that iv chloramphenico l produces peak plasma concentrations which are on average twice those after im injection of the same dose, due principally to a smaller V(d )ss. Cl-p is uninfluenced by route of administration and is determined more by hepatic metabolism than renal excretion. Intramuscular treatm ent may result in sub-therapeutic chloramphenicol concentrations initi ally, but continued regular iv dosing is more likely to produce levels at which bone marrow toxicity occurs.