Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine



Aims Concentrations in the cerebrospinal fluid (CSF) are a useful approximation to the effect site for drugs like morphine. However, CSF samples, are available only in rare circumstances. If they can be obtained they may provide important insights into the pharmacokinetics/pharmacodynamics of opioids.

Methods Nine neurological and neurosurgical patients (age 19–69 years) received 0.5 mg kg−1 morphine sulphate pentahydrate as an intravenous infusion over 30 min. Plasma and CSF were collected for up to 48 h. Concentration time-course and interindividual variability of morphine (M), morphine-3-glucuronide (M3G) and morphine-6 glucuronide (M6G) were analysed using population pharmacokinetic modelling.

Results While morphine was rapidly cleared from plasma (total clearance = 1838 ml min−1 (95% CI 1668, 2001 ml min−1)) the glucuronide metabolites were eliminated more slowly (clearance M3G = 44.5 ml min−1 (35.1, 53.9 ml min−1), clearance M6G = 42.1 ml min−1 (36.4, 47.7 ml min−1)) and their clearance could be described as a function of creatinine clearance. The central volumes of distribution were estimated to be 12.7 l (11.1, 14.3 l) for morphine. Transfer from the central compartment into the CSF was also rapid for M and considerably slower for both glucuronide metabolites. Maximum concentrations were achieved after 102 min (M), 417 min (M3G) and 443 min (M6G). A P-glycoprotein exon 26 polymorphism previously found to be linked with transport activity could be involved in CSF accessibility, since the homozygous mutant genotype was associated (P < 0.001) with high maximum CSF concentrations of M but not M3G or M6G.

Conclusions From the population pharmacokinetic model presented, CSF concentration profiles can be derived for M, M3G and M6G on the basis of dosing information and creatinine clearance without collecting CSF samples. Such profiles may then serve as the link between dose regimen and effect measurements in future clinical effect studies.