Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol.

Gastrointestinal absorption of several beta-blockers is inhibited by citrus juices, although molecular mechanism(s) lying on their small intestinal absorption has not yet been identified. Here, we attempted to demonstrate involvement of both influx and efflux transporters in vivo in gastrointestinal absorption of celiprolol in mice. Plasma concentration of celiprolol (3 mg/kg) after oral administration was mostly under the limit of quantification in wild mice, whereas that in mdr1a/b knockout (mdr1a/b(-/-)) mice was much more obvious, indicating P-glycoprotein-mediated efflux. Then, the oral absorption of celiprolol in mdr1a/b(-/-) mice was further examined to investigate influx transport mechanism with avoiding effect of P-glycoprotein. Coadministration of bromosulfophthalein (BSP), an inhibitor of various influx transporters including organic anion transporting polypeptide (OATP) reduced plasma celiprolol concentration. Inhibition by BSP of celiprolol uptake from apical membranes was confirmed in Ussing-type chamber of small intestinal tissues. Uptake of celiprolol by human small intestinal transporter OATP-A/1A2 was also confirmed in Xenopus Laevis oocytes. Interestingly, OATP-A/1A2 accepts various beta-blockers including acebutolol, atenolol and sotalol, oral absorption of which is inhibited by coadministration of citrus juice or telithromycin in human. Taken together, these findings have suggested fundamental role of influx transport system(s) in oral absorption of celiprolol.

Reproducibility and consistency of the responses to supine bicycle ergometry; evaluation in conjunction with beta 1-adrenoceptor occupancies.

A protocol is presented for supine bicycle ergometry in healthy subjects, which aims for a target increase of heart rate (HR = 140 beats min-1) after 4 min cycling under constant load. The required load is selected from a pre-study ergometry with stepwise increasing load. Repeated testing with this protocol was shown to yield highly reproducible ergometric HR-responses. Because of their high reliability, the ergometric endpoints and increments permit a highly sensitive comparison of beta 1-adrenoceptor antagonism across dose and time within a given compound. The relationship between the changes of the ergometric rise of HR and the beta 1-adrenoceptor occupancy (estimated from radioreceptor assay data) permits to evaluate the ergometric efficiency of different beta-adrenoceptor antagonists across time and doses and to identify eventual differences that do not relate primarily to the extent of beta 1-adrenoceptor antagonism itself.

Partial agonist activity of celiprolol.

Celiprolol given intravenously (i.v.) to pithed rats in the dose range of 0.1-10,000 micrograms/g produced a dose-dependent increase in heart rate (HR) which was greatest (123 beats/min) at 1,000-3,000 micrograms/kg. This partial agonist effect was blocked by the selective beta 1-adrenoceptor antagonist CGP 20712A. Celiprolol also produced a vasodepressor effect in this dose range which was abolished by the relatively selective beta 2-adrenoceptor antagonist ICI 118551 but not CGP 20712A. The magnitude of this intrinsic sympathomimetic activity (ISA) response was not significantly altered by reserpine pretreatment. Celiprolol also antagonised the effects of isoprenaline 0.05 microgram/kg on HR and blood pressure (BP). The beta 1 selectivity of celiprolol as an antagonist in pithed rats (beta 1/beta 2 = 340:1) was similar to that observed in studies with isolated guinea pig atria and trachea (beta 1/beta 2 = 63:1), both being considerably greater than that observed with atenolol. Celiprolol, however, like atenolol, potentiated the bronchoconstrictor responses to histamine (3 micrograms/kg). Metabolic studies of rats and human urine failed to show significant amounts of potentially vasoactive metabolites. These data are consistent with celiprolol acting as both a beta 1- and beta 2- adrenoceptor partial agonist.

Effect of pretreatment with the selective beta 1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and beta-adrenoceptor subtype specific occupancy of celiprolol in healthy man.

The cardiovascular effects at rest and during exercise and beta 1- and beta 2-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p.o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p.o., using a placebo-controlled, 2-way cross-over design. The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median beta 1-RRA and beta 2-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to beta 1-adrenoceptors, moderately to beta 2-adrenoceptors, acts as beta 1-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect beta 1-adrenergic agonism, but which might reflect beta 2-adrenergic agonism.

Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium.

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.