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.
