Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters

Johannes Matthaei, Mladen V Tzvetkov, Valerie Gal, Cordula Sachse-Seeboth, Daniel Sehrt, Jakob B Hjelmborg, Ute Hofmann, Matthias Schwab, Reinhold Kerb, Jürgen Brockmöller, Johannes Matthaei, Mladen V Tzvetkov, Valerie Gal, Cordula Sachse-Seeboth, Daniel Sehrt, Jakob B Hjelmborg, Ute Hofmann, Matthias Schwab, Reinhold Kerb, Jürgen Brockmöller

Abstract

Background: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors. In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters.

Methods: Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs. The oral clearance of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within- and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1.

Results: Talinolol clearance varied approximately ninefold in the studied sample of healthy volunteers. The correlation of clearances between siblings was not significantly different for the monozygotic and dizygotic pairs. All data analyses consistently showed that variation of talinolol pharmacokinetics was mainly determined by environmental effects. Structural equation modeling attributed 53.5 % of the variation of oral clearance to common environmental effects influencing both siblings to the same extent and 46.5 % to unique environmental effects randomly affecting individual subjects. Talinolol pharmacokinetics were significantly dependent on sex, body mass index, total protein consumption, and vegetable consumption.

Conclusions: The twin study revealed that environmental factors explained much more of the variation in pharmacokinetics of talinolol than genetic factors.

Trial registration: European clinical trials database number: EUDRA-CT 2008-006223-31. Registered 26 September 2008. ClinicalTrials.gov number: NCT01845194 .

Keywords: ABCB1; ABCC2; BCRP; Heritability; MDR1; MDR5; MRP2; P-glycoprotein; Talinolol; Twin study.

Figures

Fig. 1
Fig. 1
a Variation in Cl/F for the subjects who performed all three study days (SD) of the 50 mg talinolol study phase. b, c Correlation of the Cl/F after administration of 50 mg talinolol for all siblings from MZ (n = 42) and DZ (n = 13) twin pairs. d, e Correlation of the AUC7h after administration of 50 mg talinolol (filled circles) and the dose-adjusted AUC7h after administration of 2.5 mg talinolol (empty circles) for all analyzed twins. For b–d the Pearson correlation coefficients, the coefficients of determination, and the p-values are given. MZ monozygotic twin pairs, DZ dizygotic twin pairs, Cl/F total plasma clearance/bioavailability, AUC7h area under the curve in the first 7 h after application, SD study day
Fig. 2
Fig. 2
a, b Concentration time curves of one study day of the 50 mg talinolol study phase (a) and the 2.5 mg talinolol study phase (b). c Correlation of the AUC7h after the administration of 50 mg and 2.5 mg talinolol. Shown are all 72 individuals who received both dosages. AUC7h area under the curve in the first 7 hours after application

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