Linked Life Data

11999291

Source:http://linkedlifedata.com/resource/pubmed/id/11999291

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2002-5-9
pubmed:abstractText
Clinical cases have been reported of tacrolimus (FK506)-induced QT prolongation. We have previously demonstrated sustained QT prolongation by FK506 in guinea pigs. Herein, we aimed to conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis of FK506, using a model involving the myocardial compartment. The pharmacokinetics of FK506 and its effects on QTc intervals were investigated in guinea pigs. In the pharmacokinetic study, whole blood and ventricular FK506 concentrations were analyzed, using a 4-compartment model during and after intravenous infusion of FK506 (0.01 or 0.1 mg/hr/kg). Subsequently, the concentration-response relationship between ventricular FK506 concentration and change in QTc interval was analyzed, using the maximal effect (Emax) model. Pharmacokinetic profiles of FK506 showed a delayed distribution of FK506 into the ventricle. Furthermore, the observed QT prolongation paralleled the ventricular FK506 concentrations, with no lag-time between the two. The Emax model successfully described the relationship between changes in QTc interval and ventricular FK506 concentrations. In conclusion, the PK/PD model where the myocardial drug concentration of FK506 was linked with its adverse effect could describe, for the first time, the anti-clockwise hysteresis observed in the relationship between blood FK506 concentration and QTprolongation. Such a hysteresis pattern for QTprolongation might be caused, therefore, mainly by the delayed disposition of FK506 to ventricular myocytes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1567-567X
pubmed:author
pubmed:issnType
Print
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
533-54
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Quantitative relationship between myocardial concentration of tacrolimus and QT prolongation in guinea pigs: pharmacokinetic/pharmacodynamic model incorporating a site of adverse effect.
pubmed:affiliation
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Japan.
pubmed:publicationType
Journal Article