Delving into the Latest Updates on Pafenolol with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

H-138-03, H-138/03

Target

β-adrenoceptors

Mechanism

β-adrenoceptors antagonists(Beta adrenergic receptors antagonists)

Therapeutic Areas

Cardiovascular Diseases

Active Indication-

Inactive Indication

Arrhythmias, Cardiac

Originator Organization

AstraZeneca PLC

Active Organization-

Inactive Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Hassle Free Taxes LLC

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC18H31N3O3

InChIKeyPKWZWSXSCKVUJB-UHFFFAOYSA-N

CAS Registry75949-61-0

The potential absorption-limiting effect of intestinal efflux transporters such as P-glycoprotein (P-gp) has been well recognized, primarily based on results of numerous Caco-2 cell studies showing that flux, permeability, or transport clearance of drugs from the basolateral to the apical (B --> A) compartment is greater than that from the apical to the basolateral (A --> B) compartment. Except for very limited examples such as celiprolol, talinolol, pafenolol and paclitaxel, the potential clinical impact of these transporters on oral absorption of the vast number of commonly prescribed drug substrates in humans has not been closely examined to date.

OBJECTIVE:

To evaluate whether these efflux transporters may play a significant role in limiting oral absorption of 13 commonly used drugs (digoxin, etoposide, felodipine, fexofenadine, furosemide, indinavir, losartan, nadolol, propranolol, ritonavir, saquinavir, tacrolimus, and verapamil) in humans.

METHODS:

Drug absorption properties such as the rate (as judged by the Cmax and tmax) and extent (as judged by AUC or urinary excretion of drugs) of absorption as a function of dose, as well as the completeness of oral absorption were obtained from the literature.

RESULTS:

The absorption properties of these 13 drugs are not consistent with absorption-retarding expectations from in vitro studies because they all show apparent dose-independent kinetics in absorption or bioavailability and completeness of oral absorption is shown for most of the drugs evaluated.

CONCLUSIONS:

In spite of being substrates of intestinal efflux transporters such as P-gp, the in vivo oral absorption of 13 drugs examined apparently is not significantly impeded by efflux transporters. Thus, there may exist an apparent discrepancy between in vitro "expectations" and in vivo results; potential reasons for this are discussed. The present findings, however, do not de-emphasize potential in vivo importance of efflux transporters in affecting (increasing or decreasing) oral absorption of certain substrate drugs, especially those with low to moderate intestinal permeability and with low therapeutic index, or the importance of efflux transporters in the study of mechanisms of drug absorption and some potentially clinically significant drug-drug and drug-food interactions.

01 Nov 2000·International journal of clinical pharmacology and therapeuticsQ4 · MEDICINE

Similarity in the linear and non-linear oral absorption of drugs between human and rat

Q4 · MEDICINE

Article

Author: Hyun-Young Jeong ; S. M. Chung ; C. Ma ; T. C. Wu ; W. L. Chiou

OBJECTIVE:

The main aim of this study was to provide a simple, pharmacokinetic rationale for great similarity in the extent (Fab) of gastrointestinal absorption of about 100 different, diverse compounds between human and the rat in linear dosing range, and to test the general applicability of a novel empirical method to correlate the non-linear Fab between the human and the rat by normalizing doses by body surface area (BSA) or body weight 0.67.

METHOD:

The mean small intestinal transit time (t) of 36 rats was estimated from the reported study, and this was used to compare with that in humans. The reported great similarity in apparent first-order absorption rate constants (k) of seven structurally diverse compounds between the two species were obtained. Extensive computer search was made and non-linear Fab data for the two species were obtained for chlorothiazide, acyclovir, miglitol and pafenolol.

RESULTS:

The mean t for rats was estimated to be 3.32 h which is almost identical to that reported in humans. The great similarity in Fab between human and rat in linear absorption range can be rationalized by similar t and k between the two species. The markedly different Fab vs dose/kg of body weight profiles between human and rat for the four drugs showing dose-dependent Fab were found to collapse when doses were normalized by BW0.67.

CONCLUSION:

For Fab not limited by the solubility problem, the great similarity in Fab between human and rat in linear absorption range can be rationalized by the similar t and k. For non-linear Fab drugs, great similarity in Fab can also be obtained between human and rat when doses are normalized by BSA or BW0.67. Regardless of absorption properties (active, passive or facilitated), similar Fab between the two species may be generally obtained when doses used in humans are about 5 to 7 times lower than that in rats. The above findings may be valuable in drug development.

01 Nov 1993·British journal of pharmacologyQ2 · MEDICINE

Transport of celiprolol across human intestinal epithelial (Caco‐2) cells: mediation of secretion by multiple transporters including P‐glycoprotein

Q2 · MEDICINE

Article

Author: Shiu-Ming Kuo ; John Ziemniak ; Johan Karlsson ; Per Artursson

1. The transepithelial transport of the beta-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2. 2. The basal-to-apical transport (secretion) of [14C]-celiprolol (50 microM) was 5 times higher than apical-to-basal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-to-apical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3. Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 +/- 0.23 mM and Vmax of 113 +/- 11 pmol/10(6) cells min-1. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4. The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5. The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N1-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems. 6. The secretion of celiprolol was also inhibited by other beta-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.

100 Deals associated with Pafenolol

Login to view more data