Rifampicin reduces plasma concentrations of celiprolol.
OBJECTIVE
The beta-adrenoceptor-blocking agent celiprolol undergoes negligible metabolism, but is a substrate for P-glycoprotein. Our objective was to investigate the effects of rifampicin on the pharmacokinetics of celiprolol in healthy subjects.


METHODS
In a randomized cross-over study with two phases and a washout of 4 weeks, ten healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 200-mg dose of celiprolol was administered orally. The plasma concentrations of celiprolol and the excretion of celiprolol into urine were measured up to 33 h after its dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 h later. MDR1 (P-glycoprotein) genotype was assessed with respect to polymorphisms in exon 21 (G2677T/A) and in exon 26 (C3435T).


RESULTS
Rifampicin pretreatment reduced the median area under the plasma celiprolol concentration-time curve AUC(0-33 h) to 0.44-fold [90% confidence interval (CI), 0.27-0.86], relative to the placebo. The median peak plasma concentration, the time of peak concentration, and the elimination half-life of celiprolol were not significantly changed by rifampicin. During the rifampicin phase, the median amount of celiprolol excreted into urine was decreased by 47% ( P<0.05) and celiprolol renal clearance increased by 19% ( P<0.05) compared with the placebo phase. There were great inter-individual differences in the extent of rifampicin-celiprolol interaction. However, no association was found between the MDR1 polymorphisms and the degree of interaction between rifampicin and celiprolol. No significant differences were observed in hemodynamic parameters between the phases.


CONCLUSIONS
Rifampicin pretreatment reduces plasma celiprolol concentrations, possibly by induction of the efflux transporter P-glycoprotein, particularly in the intestinal wall, which leads to decreased absorption of celiprolol.
Lilja
J J
JJ
Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, 00290 Helsinki, Finland. jari.lilja@hus.fi
Niemi
M
M
Neuvonen
P J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000319:Adrenergic beta-Antagonists / Q000097:blood* / Q000493:pharmacokinetics; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D019540:Area Under Curve; D017272:Celiprolol / Q000097:blood* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012293:Rifampin / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D000904:Antibiotics, Antitubercular; D017272:Celiprolol; D012293:Rifampin