REASONS OF POOR BIOAVAILABILITY

Poor aqueous solubility : In most of cases poor bioavailabiity of drugs is assoiated with the poor aqueous solubility of drugs.The contents of gastrointestinal tract are aqueous and hence a drug having poor aqueous solubility has a low saturation solubility which is typically correlated with a low dissolution velocity, resulting in poor oral bioavailability¹.

Inappropriate partition coefficient:Drugs which have too aqueous solubility are not able permeate the biologica membrane and which have the too lipophili are not dissolve GI aqueous environment.So,The drugs should be have the both the hydrophilliity and lipophiliity for get good absorption.Drugs having partition coefficient (log P) value in the range of 1 to 3 shows good passive absorption across lipid membranes, and those having log Ps greater than 3 or less than 1 have often poor transport characteristics.

First-pass metabolism : High first pass metabolism leads to poor bioavailabiity.Orally administered drugs must pass through the intestinal wall and then through the portal circulation to the liver; both are common sites of first pass metabolism (metabolism of a drug before it reaches systemic circulation). Thus, many drugs may be metabolized before adequate plasma concentrations are reached resulting in poor bioavailability. The enterocyte expresses many of the metabolic enzymes that are expressed in the liver.

These include cytochromes P450, UDP-glucuronyltransferases, sulfotransferases, and esterases¹.

Degradation due to low pH in stomach Most drug substances are fairly stable at the neutral pH values found in the small intestine (disregarding enzymatic degradation) but can be unstable at low pH values found in the stomach. Examples of drugs that are very acid-labile are various penicillins, erythromycin and some of its analogs , and the 2', 3'-dideoxypurine nucleoside anti-AIDS drugs . Knowledge of the stability of a drug in the pH range of 1-2 at 37degC is important in the formulation design of potentially acidlabile drugs . At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oralbioavailability (7-9%) might be due to decomposition of foscarnet in gastric acid².

Interaction with food Drugs that undergo a significant first-pass metabolism with a lower bioavailability ranging from 5% to 30% may be affected to a greater degree by grapefruit juice . Calcium, as well as food and dairy products containing high concentrations of calcium, may decrease the absorption of tetracyclines due to chelate formation in the gut.

Insufficient time for absorption in the gastrointestinal tract is a common cause of low bioavailability. If the drug (eg. highly ionized and polar drugs) does not dissolve readily or cannot penetrate the epithelial membrane during its residence time in the gastrointestinal tract, its bioavailoavailability tends to be highly variable as well as low³.

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References:

1. L. Shargel, A.B. Yu, (1999). Applied biopharmaceutics & pharmacokinetics (4th edition) New York: McGraw-Hill. ISBN 0-8385-0278-

2. G.Suresh, K.Manjunath, V.Venkateswarlu, V. Satyanarayana, Preparation, Characterization, and In Vitro and In Vivo Evaluation of Lovastatin Solid Lipid Nanoparticles, AAPPharmSciTech 2007; 8 (1) Article 24, E1-E9.

3. M.S. Gogate, Erythromycin monograph, in chemical stability of Pharmaceuticals: A handbook for Pharmacists, 2nded. (K.A. Connors, G. L. Amidon, V.J.Stella, eds), 457-463, John Wiley and sons, Newyork, 1986, and references therein