A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels.
Risperidone (R) is metabolized to 9-hydroxyrisperidone (9-OHR) by cytochrome P450 2D6 (CYP2D6). The main objective of this naturalistic study was to investigate the variables associated with two plasma ratios: the plasma R:9-OHR concentration ratio and the total concentration-to-dose (C:D) ratio. These ratios were studied as continuous measures by linear regression analyses and as three dichotomous variables in logistic regression analyses: R:9-OHR ratio >1 (indicative of lack of CYP2D6 activity), C:D ratio >14 (indicative of diminished R elimination), and C:D ratio <3.5 (indicative of increased R elimination). Plasma R levels; genotypes for CYP2D6, CYP3A5; and ABCB1 genes, and co-medication, including CYP inhibitors and CYP3A inducers, were studied in 277 patients. Almost all CYP2D6 poor metabolizers (PMs) had an inverted R:9-OHR ratio (>1). Having a CYP2D6 PM phenotype was strongly associated with a C:D ratio >14 (OR=8.2; 95% confidence interval [CI]=2.0-32.7), indicating diminished R elimination. CYP2D6 ultrarapid metabolizers (UMs) did not exhibit an increased R elimination. Some ABCB1 (or MDR1) variants were significantly associated with increased R:9-OHR ratios and decreased C:D ratios, but the results were neither consistent nor robust. Taking CYP inhibitors was significantly associated with a C:D ratio >14 (OR=3.8; CI=1.7-8.7) and with an inverted R:9-OHR ratio. Taking CYP3A inducers was significantly associated with a C:D ratio <3.5 (OR=41.8; CI=12.7-138), indicating increased R elimination. Female gender and old age appeared to be associated with a lower R elimination. Our study indicated that the CYP2D6 PM phenotype may have a major role in personalizing R doses, whereas the CYP3A5 PM phenotype probably has no role. CYP inducers and inhibitors appear to be relevant to R dosing. New studies are needed, particularly to further assess the role of the CYP2D6 UM phenotype and ABCB1 variants in R pharmacokinetics.
Leon
J de
Jd
University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, Kentucky. jdeleon@uky.edu
Susce
M T
MT
Pan
R-M
RM
Wedlund
P J
PJ
Orrego
M L
ML
Diaz
F J
FJ
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000375:Aging / Q000378:metabolism; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000097:blood / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism*; D018967:Risperidone / Q000097:blood / Q000493:pharmacokinetics*; D012737:Sex Factors
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007555:Isoxazoles; D027361:Organic Anion Transporters; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D018967:Risperidone; D000068882:Paliperidone Palmitate