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.
Siegmund
Werner
W
Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Friedrich Loeffler Strasse 23d, D-17487 Greifswald, Germany. siegmuw@mail.uni-greifswald.de
Ludwig
Karen
K
Engel
Georg
G
Zschiesche
Michael
M
Franke
Gerd
G
Hoffmann
Anna
A
Terhaag
Bernd
B
Weitschies
Werner
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D016001:Confidence Intervals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011412:Propanolamines / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011412:Propanolamines; D013607:Tablets; C011550:talinolol