Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-inducedhypoalbuminemia - A model to explore the effects of decreased protein binding capacity on highly bound drugs

Background: Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on t heir pharmacologic effects has never been investigated. The authors determi ned the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongl y to albumin in postsurgical patients with hydroxyethyl starch-induced hypo albuminemia. Methods: Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age ( +/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteer s received a 2-g ceftriaxone dose infused over a 15-min period, Fourteen ve nous blood samples were collected during the 24-h study period. Free ceftri axone concentrations were determined by ultrafiltration. Antibiotic concent rations In plasma and ultrafiltrate were measured by ion-paired reversed-ph ase chromatography. The pharmacokinetic parameters derived from total and f ree antibiotic concentrations were determined using a noncompartmental meth od Data are expressed as median and range. Results: The pharmacokinetic parameters derived from total ceftriaxone conc entrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0.11-0.29 l/kg) in patients, compared with 0.15 l/kg (ran ge, 0.13-0.22 l/kg) in volunteers, The area under the free ceftriaxone conc entration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h . mg(-1) . l(-1); P = 0. 03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16.7; range, 12.6-21.4 vs, median, 1 1.1; range, 6.0-19.0 h; P = 0.03). Conclusions: Compared with healthy volunteers, patients with iatrogenic hyp oalbuminemia have higher free ceftriaxone concentrations during the 24 h af ter antibiotic administration, This modification increases drug distributio n into extravascular space and may enhance effectiveness.