Bisoprolol fumarate is a synthetic, beta1-selective (cardioselective) adrenoceptor blocking agent. The chemical name for Bisoprolol fumarate is (±)-1-[4-[[2-(1-Methylethoxy) ethoxy]methyl] phenoxy]-3-[(1-methylethyl)amino]-2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its empirical formula is (C18H31NO4)2•C4H4O4 and its structure is:β-agonist Powder
Bisoprolol fumarate has a molecular weight of 766.97. It is a white
crystalline powder which is approximately equally hydrophilic and
lipophilic, and is readily soluble in water, methanol, ethanol, and
chloroform.
Bisoprolol Fumarate Tablets, USP is available as 5 and 10 mg tablets for oral administration.
Inactive
ingredients include colloidal silicon dioxide, partially pregelatinized
starch, crospovidone, anhydrous dibasic calcium phosphate,
hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, titanium dioxide and talc.
Bisoprolol fumarate
is a beta1-selective (cardioselective) adrenoceptor blocking agent
without significant membrane stabilizing activity or intrinsic
sympathomimetic activity in its therapeutic dosage range.
Cardioselectivity is not absolute, however, and at higher doses (> 20
mg) Bisoprolol fumarate also inhibits beta2-adrenoceptors, chiefly
located in the bronchial and vascular musculature; to retain selectivity
it is therefore important to use the lowest effective dose.
Pharmacokinetics and Metabolism
The absolute bioavailability after a 10 mg oral dose of Bisoprolol fumarate is about 80%. Absorption is not affected by the presence of food. The first pass metabolism of Bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once daily dosing with Bisoprolol fumarate results in less than twofold intersubject variation in peak plasma levels. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population. Steady state is attained within 5 days of once daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing. Plasma concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects. In patients with cirrhosis of the liver, the elimination of Bisoprolol fumarate is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.
