Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

L M Nielsen; E Sverrisdóttir; T B Stage; S Feddersen; K Brøsen; L L Christrup; A M Drewes; A E Olesen

doi:10.1016/j.ejps.2016.12.039

Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

Eur J Pharm Sci. 2017 Mar 1:99:337-342. doi: 10.1016/j.ejps.2016.12.039. Epub 2017 Jan 4.

Authors

L M Nielsen¹, E Sverrisdóttir², T B Stage³, S Feddersen⁴, K Brøsen³, L L Christrup², A M Drewes⁵, A E Olesen⁶

Affiliations

¹ Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
² Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
⁴ Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
⁵ Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁶ Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. Electronic address: aneso@rn.dk.

PMID: 28063968
DOI: 10.1016/j.ejps.2016.12.039

Abstract

Aim: A high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers.

Methods: Pharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (k_tr), clearance (CL), and volume of distribution (V_D). The area under the plasma concentration-time curve (AUC_0-150min) and the maximum plasma concentration (C_max) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation ("the cold pressor test" where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined.

Results: Neither AUC_0-150min, k_tr, CL, nor V_D were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05).

Conclusions: In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

Keywords: Healthy volunteers; Interindividual variability; Morphine; Pharmacogenetics; Pharmacokinetics.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / genetics
Adult
Cross-Over Studies
Double-Blind Method
Female
Genotype
Glucuronosyltransferase / genetics*
Humans
Male
Morphine / pharmacokinetics*
Octamer Transcription Factor-1 / genetics*
Polymorphism, Single Nucleotide / genetics*
Randomized Controlled Trials as Topic
Young Adult

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Octamer Transcription Factor-1
POU2F1 protein, human
Morphine
UGT2B7 protein, human
Glucuronosyltransferase