Linked Life Data

20530222

Source:http://linkedlifedata.com/resource/pubmed/id/20530222

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2010-8-19
pubmed:abstractText
This study was conducted to investigate the effect of the reduced function allele CYP2D6*10, which can be the cause of an intermediate metabolizer (IM), on tolterodine pharmacokinetics. Tolterodine is mainly metabolized to an active 5-hydroxymethyl metabolite (5-HM) by CYP2D6, and 5-HM is also metabolized by CYP2D6. Asian and white healthy volunteers (n = 108) received once daily multiple doses of tolterodine, and the serum concentrations of tolterodine and 5-HM were measured. All subjects were genotyped for CYP2D6. Tolterodine exposures [area under the curve (AUC)] increased in order of CYP2D6*1/*1 [extensive metabolizer (EM)] < CYP2D6*1/*10 < CYP2D6*10/*10 < CYP2D6*5/*10. It was expected that the order of 5-HM exposure would be reversed. However, the 5-HM AUC increased in the same order as that of tolterodine. This phenomenon was explained by considering CYP2D6 mediation of both production and elimination of 5-HM. The tolterodine and 5-HM exposures in CYP2D6*10/*10 were statistically higher than those for CYP2D6*1/*1 (3- and 1.5-fold, respectively). In CYP2D6*4/*4 [poor metabolizer (PM)], 5-HM was not produced and tolterodine exposure was 20-fold higher than that in CYP2D6*1/*1. With consideration for higher protein binding of tolterodine than 5-HM, the exposure as a sum of the unbound fraction of tolterodine and 5-HM (active moiety) in CYP2D6*10/*10 was 1.8-fold higher than that in CYP2D6*1/*1 and was also higher than that in CYP2D6*4/*4. Simulation using the values of EM and PM demonstrated that the maximum possible active moiety exposure was around the observed values of CYP2D6*5/*10, which were 1.9-fold higher than those for CYP2D6*1/*1. This is the first report to provide an example in which the IM shows higher exposure to pharmacological active moiety than the EM and PM.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1521-009X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1456-63
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Effect of the CYP2D6*10 genotype on tolterodine pharmacokinetics.
pubmed:affiliation
Clinical Pharmacology, Clinical Research, Tokyo Laboratories, Pfizer Japan Inc., 3-22-7 Yoyogi, Shibuya-ku, Tokyo, Japan. masayo.oishi@pfizer.com
pubmed:publicationType
Journal Article