Metabolites, measurement bioavailability studies

Tucker G, Rostami A, Jackson P. Metabolite measurement in bioequivalence studies theoretical considerations. In Midha KK, Blume HH, eds. Bio-Intemational Bioavailability, Bioequivalence and Pharmacokinetics. Stuttgart Medpharm Scientific Publishers, 1993 163-170. 

If an intravenous formulation can be developed, a crossover absolute bioavailability study in healthy volunteers can provide an unambiguous measure of clearance and volume of distribution as well as absolute bioavailability and absorption kinetics of the clinical formulation. Comparison of metabolite pharmacokinetics after oral and intravenous administration can provide information on first-pass metabolism. 

For bioavailability studies, the parent compound or the active moiety and the active metabolites should be measured if analytically feasible. For bioequivalence studies, the measurement of the parent compound is desirable, unless the parent drug levels in the plasma or serum are too low to allow reliable measurements. In addition to measuring the parent, the measurement of the metabolite is important when it contributes to either safety or efficacy of the drug product. The bioequivalence criterion is applied to the parent with supportive evidence from the metabolite measurements. Similarly, measurement of enantiomers or racemate may be necessary as appropriate. 

Studies that investigate the bioavailability of resveratrol in humans are scarce. Moreover, the research in this area is quite recent. It has been summarized in Table 13.5. The experimental approaches have been improved with the use of new analytical techniques such as mass spectrometry to identify and quantify metabolites present in very low concentrations. Resveratrol and its metabolites have been measured in several biofluids plasma or serum, urine, LDL, and feces. 

Bioavailability. Bioavailability has become an important part of the QA effort to prove that the product maintains its strength, safety, purity, and efficacy during its shelf life. Since bioavailability was introduced, the scientist has not been satisfied with chemical equivalence between batches of product, and this expanded the QA effort. The study of bioavailability makes it necessary to know how the body s physiology and biochemistry are affected by the drug molecule s availability within it. The drug s concentration in the body fluids, its ability to bind protein, its metabolic rate, its ability to present the active metabolite at the needed site of action, and the body s excretion rate are the tools used to measure the drug s bioavailability. 

Another type of study is described by the term ADME (absorption, distribution, metabolism, and elimination). The rate of absorption describes how fast the drug substance enters the bloodstream and is a measure of bioavailability. The distribution in the body is measured to confirm that the substance reaches the target organ and that it does not accumulate in other organs. Metabolism is the chemical conversion of the substance in the body to other compounds and elimination describes how fast and by which route the substance and its metabolites are eliminated from the body. 

Human data on phytochemicals concentrate largely on measurement of urinary metabolites in combination with stable isotope labeling this is a valid method for studying mineral bioavailability, since the difference between the amount absorbed and excreted is retained in the body and, excluding the amount stored in body pools, assumed to be bioavailable. 

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