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

TY - JOUR

T1 - Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

AU - Nielsen, L M

AU - Sverrisdóttir, E

AU - Stage, T B

AU - Feddersen, S

AU - Brøsen, K

AU - Christrup, L L

AU - Drewes, A M

AU - Olesen, A E

N1 - Copyright © 2017 Elsevier B.V. All rights reserved.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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 (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0-150min) and the maximum plasma concentration (Cmax) 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 AUC0-150min, ktr, CL, nor VD 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.

AB - 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 (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0-150min) and the maximum plasma concentration (Cmax) 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 AUC0-150min, ktr, CL, nor VD 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.

KW - ATP Binding Cassette Transporter, Sub-Family B

KW - Adult

KW - Cross-Over Studies

KW - Double-Blind Method

KW - Female

KW - Genotype

KW - Glucuronosyltransferase

KW - Humans

KW - Male

KW - Morphine

KW - Octamer Transcription Factor-1

KW - Polymorphism, Single Nucleotide

KW - Randomized Controlled Trials as Topic

KW - Young Adult

KW - Journal Article

U2 - 10.1016/j.ejps.2016.12.039

DO - 10.1016/j.ejps.2016.12.039

M3 - Journal article

C2 - 28063968

SN - 0928-0987

VL - 99

SP - 337

EP - 342

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

ER -