Dj. Cordato et al., Pharmacokinetics of thiopental enantiomers during and following prolonged high-dose therapy, ANESTHESIOL, 91(6), 1999, pp. 1693-1702
Citations number
32
Categorie Soggetti
Aneshtesia & Intensive Care","Medical Research Diagnosis & Treatment
Background: Thiopental is used as a racemate; however, this is not generall
y recognized. During conditions of prolonged high-dose therapy, the pharmac
okinetics of thiopental may become nonlinear, but whether this derives from
one or both enantiomers has not been evaluated, The authors determined the
pharmacokinetics of R- and S-thiopental and serum concentrations of R- and
S-pentobarbital from prolonged high-dose infusion of thiopental for neurop
rotection.
Methods: Twenty patients received a mean thiopental dose of 41.2 g over a m
ean duration of 95 h, R- and S-thiopental enantiomer serum concentration-ti
me data from 18 patients were fitted with two models: a linear one-compartm
ent model with first-order output, and a nonlinear one-compartment model wi
th Michaelis-Menten output.
Results: Nonlinear models were preferred in 16 of 18 patients. Paired analy
sis indicated that steady state clearance (Cl-ss) and volume of distributio
n (V-d) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001: an
d 313 vs. 273 1, P < 0.0005, respectively); maximal rate of metabolism (V-m
) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg . l(-1) . h(-1)
, P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.
8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, res
pectively, P < 0.0001). The differences in mean Cl-ss, V-d and V-m were not
significant when adjusted by f(u). Plasma concentrations of R- and S-pento
barbital were relatively small and unlikely to be of clinical significance.
Conclusion: The pharmacokinetics of R- and S-thiopental became nonlinear at
these doses. The pharmacokinetic differences between R- and S-thiopental,
although small, were statistically significant and were influenced by the h
igher f(u) of R-thiopental.