Bioavailability of a drug

The bioavailability of a drug is defined as the fraction of the dose of a drug that is found in general circulation (see Section 8.5). It is influenced by such factors as ADME. Bioavailability is not constant but varies with the body s physiological condition. 

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The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during en-terohepatic recirculation may have altered systemic availability in children up to approximately 3 years of age because of delayed maturation of conjugation. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

What factors influence the bioavailability of a drug following its oral administration ... 

Thus, the oral bioavailability of a drug is determined by the amount absorbed from the GIT, the fraction escaping first-pass extraction by the gut, and the fraction escaping first-pass extraction by the liver. It is summarized by the following equation ... 

Consequently, the gut wall can exert a significant outcome on the overall oral bioavailability of a drug molecule. It is now time to consider the enzymes and transporters, which combine to express gut wall first-pass extraction. 

Oral bioavailability of a drug is primarily dependent upon its rate and extent of drug absorption and systemic clearance. Systemic clearance is primarily composed of hepatic, renal and biliary clearance. The PK properties are in turn directly impacted by the drug s physical properties, such as, log P, log D and pKa. The physical properties are in turn a function of the compound s structure, molecular weight, number of hydrogen bond donors and acceptors, and number of rotatable bonds. Oral bioavailability is the outcome from the dynamic interplay of these factors in the biological system. 

Medical scientists mainly rely on the measurement of bioavailability of a drug as a positive indicator of therapeutic equivalence, because clinical efficacy for orally administered drugs depends on the degree of absorption and the presence of the active ingredient in the blood stream. 

Why do the chemical purity and bioavailability of a drug equally important to determine the efficiency of a dosage form ... 

Presystemic elimination diminishes the bioavailability of a drug after its oral administration. Absolute bioavailability = systemically available amount/ dose administered relative bioavailability = availability of a drug contained in a test preparation with reference to a standard preparation. 

The extent of absorption of a drug can be estimated by comparing the total area under the drug concentration in the blood versus time curve or the total amount of unchanged drug excreted in the urine after administration of drug and compared to the administration of standard (standard may be an intravenous injection, where the bioavailability of a drug reaches 100%). 

Dissolution, solubility, and permeability are the three fractors that control the bioavailability of a drug for an IR drug product. Provided the inactive excipient... 

The bioavailability of a drug by various routes may also be determined by comparing the area under the curve (AUC) obtained from the plasma concentration vs. time curve after intravenous and other routes of administration 9... 

Hellriegel et al. (1996) observed a signiLcant inverse linear relationship between the bioavailability of a drug and its coefLcient of variation. An insoluble drug with very low oral bioavailability usually has a very large intersubject variability in its absorption pharmacokinetic parameters, which may result in a worrisome safety proLle or unfavorable efLcacy. 

An increasing body of evidence has shown that certain lipids and excipients found in many lipid-based formulations are capable of inhibiting both P-gp mediated drug efflux and presystemic metabolism in the enterocyte. This inhibition may increase the bioavailability of a drug coadministered with such lipid-based vehicle. 

Tear film factors [4] that can influence the ocular bioavailability of a drug are as follows ... 

The oral bioavailability of a drug (F ) may be regarded as the product of the fraction of the drug dose absorbed into and through the gastrointestinal membranes (Fabs), the fraction of the absorbed dose that passes unchanged through the gut into the hepatic portal blood (F0) and the hepatic first pass availability (Fh) (Eq. 1)... 

Since the area under the plasma concentration-time curve (AUC) for a drug is a measure of the total amount of a drug reaching the general circulatory system, the bioavailability of a drug may also be defined in terms of the AUC as ... 

All orally administered chugs must pass through the gastrointestinal tract to reach the blood and thus pass the barrier formed by the enterocytes in the intestine. For years, low first-pass bioavailability of a drug was attributed mainly to clearance via hepatic metabolism and biliary clearance or incomplete absorption in the intestine due to poor solubility or intrinsic permeability properties. Although these are important factors in determining the overall oral bioavailability of certain... 

Oral dmg product formulation and manufacturing process development can use a hierarchical approach to meeting three conditions based on, in order of importance, bioavailability, stability, and manufacturability. The bioavailability of a drug product is the most critical condition and must meet established criteria or the product is not viable. Dmg substance properties such as salt form, solubility, and particle size can significantly affect pharmacokinetic and pharmacodynamic performance of a product. The dosage form platform, formulation design, and manufacturing process can also affect the PK/PD profile of a product. Therefore, all selections must maintain the required pharmacokinetic/pharmacodynamic outcome and work within these confines to achieve a stable and robust product/process. 

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