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

Abstract

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.

Association of Single-Nucleotide Polymorhism C3435T in the ABCB1 Gene with Opioid Sensitivity in Treatment of Postoperative Pain

“…Meineke et al showed that patients carrying the TT genotype of the C3435T ABCB1 SNP, associated in other tissues with lower P-gp expression, had higher morphine cerebrospinal fluid concentrations than patients carrying the wild type C allele, associated with higher P-gp expression. These pharmacogenetics data obtained in humans are consistent with the involvement of P-gp in morphine brain disposition [17]. Age and prior use of psychotro-pic agents are associated with postoperative morphine dose requirements.…”

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…Healthy individuals genotyped as 3435TT showed a 2-fold decrease in duodenal expression (29 ). Assuming in addition that there is lower expression at the bloodbrain barrier in 3435TT genotyped individuals, this finding fits with the observed higher morphine concentrations found in the cerebrospinal fluid after intravenous injection (30 ). Consequently, lower opioid doses might be needed in these patients since they would risk side effects on normal dosages.…”

Genotypic screening of the main opiate‐related polymorphisms in a cohort of 139 sickle cell disease patients

“…For the CYP3A pathway, we genotyped two SNPs associated with a lower CYP3A activity: rs2740574 (A-392G 5 *1B allele) on the CYP3A4 gene (wild-type *1A) and rs776746 (A6986G 5 *3 allele) on the CYP3A5 gene (wild-type *1) [11]. For the UGT2B7 gene, we genotyped two SNPs associated with a lower glucuronidation of morphine and codeine: rs7438135 (A-840G) and rs73823859 (G-79A) [12,13]. For the CYP2D6 gene, we searched: (i) two polymorphisms associated with a null activity: rs892097 (G1846A 5 *4 allele) and the whole gene deletion (*5 allele), (ii) a SNP associated with an intermediate activity and very prevalent in the African population: rs28371706 (C1023T 5 *17 allele), and (iii) a gene duplication associated with an enhanced activity [8,14].…”