Variability of intestinal expression of P-glycoprotein in healthy volunteers as described by absorption of talinolol from four bioequivalent tablets.

The beta(1)-selective blocker talinolol is incompletely absorbed in man from an "absorption window" in the upper small intestine which is under control of P-glycoprotein. The following single dose, four-period, changeover study with 7 days washout in 36 healthy subjects (21 females, age 20-33 years) was designed to confirm bioequivalence of four marketed tablet formulations of talinolol with identical in vitro liberation and to deduce from the intrasubject and intersubject variability of talinolol pharmacokinetics on the variability of intestinal P-gp function. All point estimates of the primary criteria AUC(0-infinity) and C(max) for the comparison of the galenic forms were within 0.9-1.10. The 90% confidence intervals were entirely within the standard ranges of bioequivalence (0.80-1.25 for AUC(0-infinity), 0.70-1.43 for C(max)). The intra- and intersubject coefficients of variation for AUC(0-infinity) were 14.0% and 20.4-29.5%, respectively. In conclusion, the four talinolol tablets are bioequivalent in extent and rate of absorption. The low intrasubject variability of the AUC(0-infinity) after weekly administration of the tablets refers to a small intrasubject variability of the "absorption window" and elimination of talinolol that most likely depends on the expression of P-gp in the small intestine.

The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol.

BACKGROUND AND OBJECTIVES: A single-nucleotide polymorphism (SNP) of the human multidrug-resistance gene in wobble position of exon 26 reportedly predicts expression and function of P-glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, some of which lead to amino acid exchange with as yet unknown functional relevance. METHODS: In healthy white volunteers, we investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger ribonucleic acid (n = 32) and immunoreactive P-glycoprotein (n = 37) expression. Moreover, the disposition of the probe drug talinolol was evaluated in 55 subjects after oral administration (100 mg) and in 23 subjects after intravenous administration(30 mg). RESULTS: Duodenal MDR1 messenger ribonucleic acid and P-glycoprotein, as assessed by real-time polymerase chain reaction (TaqMan) and immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol disposition was not affected by the exon 26 mutation C3435T. In carriers of the TT/TA variants of G2677T/A, the area under the serum concentration-time curve values of oral talinolol were slightly but significantly elevated compared with those in carriers of at least 1 wild-type allele (P <.05, Kruskal-Wallis test; P =.014, Mann-Whitney U test). However, multiple comparisons with combinations of putative functional SNPs did not confirm a significant influence of the MDR1 genotype on talinolol disposition. CONCLUSIONS: We did not identify any influence of MDR1 genotypes on duodenal expression of P-glycoprotein and disposition of talinolol in humans.