Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: the influence of cardiac output.
BACKGROUND
Recirculatory models are capable of accurately describing first-pass pharmacokinetics and the influence of cardiac output (CO), which is important for drugs with a fast onset of effect. The influence of CO on pharmacokinetic and pharmacodynamic parameters of rocuronium in patients was evaluated using a recirculatory pharmacokinetic model.


METHODS
Fifteen patients were included to study rocuronium pharmacokinetics and pharmacodynamics. Bolus doses of rocuronium (0.35 mg/kg) and indocyanine green (25 mg) were injected simultaneously via a peripheral intravenous catheter. Blood samples were taken for 240 min from the radial artery. The force of contraction of the adductor pollicis after a train-of-four at 2 Hz every 12 s was measured. Arterial concentration-time curves of rocuronium and indocyanine green were analyzed using a recirculatory model. Pharmacodynamics were described using a sigmoid maximum effect (Emax) model.


RESULTS
The CO of the patients varied from 2.43 to 5.59 l/min. Total distribution volume of rocuronium was 17.3 +/- 4.8 l (mean +/- SD). The CO showed a correlation with the fast tissue clearance (Cl(T_f); r2 = 0.51), with the slow tissue clearance (Cl(T_s); r2 = 0.31) and with the mean transit times of rocuronium except for the mean transit time of the slow tissue compartment. The blood-effect site equilibration constant (k(e0)) was strongly correlated with CO (r2 = 0.70).


CONCLUSIONS
Cardiac output influences the pharmacokinetics, including k(e0), for rocuronium in patients. For drugs with a fast onset of effect, a recirculatory model, which includes CO, can give a good description of the relation between concentration and effect, in contrast to a conventional compartmental pharmacokinetic model.
Kuipers
J A
JA
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
Boer
F
F
Olofsen
E
E
Bovill
J G
JG
Burm
A G
AG
D000328:Adult; D000368:Aged; D000732:Androstanols / Q000493:pharmacokinetics* / Q000494:pharmacology; D000768:Anesthesia, General; D018686:Anesthetics, Intravenous; D002302:Cardiac Output; D004396:Coloring Agents / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007208:Indocyanine Green / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009467:Neuromuscular Depolarizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D010880:Piperidines; D000077208:Remifentanil; D000077123:Rocuronium
D000732:Androstanols; D018686:Anesthetics, Intravenous; D004396:Coloring Agents; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; D007208:Indocyanine Green; D000077208:Remifentanil; D000077123:Rocuronium