Alterations in dopamine clearance and catechol-O-methyltransferase activity by dopamine infusions in children

Objective: To determine the role of catechol-O-methyltransferase (COMT) in the biodisposition of pharmacologic concentrations of dopamine, Design: The study was an open-label dose escalation trial in which dopamine was employed as the sole exogenous catecholamine. The dosage was adjusted to achieve improvements in cardiac output or to augment renal function, Setting: A 16-bed pediatric intensive care unit serving both medical and surgical patients. Patients: The study was performed using 14 dopamine-treated and five untreated control patients, Children ranged in age from 16 days to 12 yrs; five of the treated patients and two of the untreated controls were female, All but one of the study patients were enrolled within 24 hrs of palliative or corrective surgery for congenital heart disease, Control patients had noncardiac surgical procedures. Both treated and control groups were similar with respect to severity of illness, as judged by Therapeutic Intervention Scoring System score, interventions: All treated patients received dopamine as a continuous intravenous infusion, Infusion rates were determined by caregivers and ranged from 3.0 to 20 mu g/kg/min. Measurements and Main Results: Serial, timed blood samples were obtained from patients and control subjects for the determination of plasma dopamine concentrations and for the determination of mononuclear cell COMT activity, Measured rates of dopamine infusion (3.0 to 18.3 mu g/kg/min) were consistently less than the nominal rates (3.0 to 20.0 mu g/kg/min) of infusion (p < .0001) due in part to calculations based on the hydrochloride salt rather than dopamine base. At similar steady-state infusion rates, plasma dopamine concentrations varied over a four-fold range, with steady-state concentrations at even the lowest infusion rate exceeding endogenous concentrations by at least ten-fold, Variations in steady-state plasma dopamine concentration reflected large age-associated variations in dopamine clearance, which was found to be saturable at concentrations of >200 ng/mL. Mononuclear cell COMT activity was assessed simultaneously in these patients. Baseline COMT activity varied over a six-fold range and was unrelated to dopamine clearance or patient age, COMT activity increased two- to six-fold in dopamine-treated patients with plasma steady-state dopamine concentrations of >100 ng/mL, Conclusions: These data demonstrate marked age and concentration-dependent differences in dopamine clearance that account for large interindividual differences in the steady-state plasma dopamine concentrations in patients receiving similar infusion rates, While concomitant variability in COMT activity is observed, the lack of correlation between dopamine clearance and COMT activity suggests that COMT is not rate-limiting for the clearance of exogenously administered dopamine.