Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction.
BACKGROUND
P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a beta1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings.


METHODS
Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1-messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years).


RESULTS
During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001).


CONCLUSIONS
Rifampin induces P-glycoprotein-mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism.
Westphal
K
K
Institute of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
Weinbrenner
A
A
Zschiesche
M
M
Franke
G
G
Knoke
M
M
Oertel
R
R
Fritz
P
P
von Richter
O
O
Warzok
R
R
Hachenberg
T
T
Kauffmann
H M
HM
Schrenk
D
D
Terhaag
B
B
Kroemer
H K
HK
Siegmund
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000494:pharmacology*; D019540:Area Under Curve; D015153:Blotting, Western; D004386:Duodenum / Q000378:metabolism*; D016145:Endoscopy, Digestive System; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology*; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D000995:Antitubercular Agents; D011412:Propanolamines; D012333:RNA, Messenger; C011550:talinolol; D012293:Rifampin