Bioavailability affecting

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Bayesian networks for multivariate reasoning about cause and effect within R D with a flow bottleneck model (Fig. 11.6) to help combine scientific and economic aspects of decision making. This model can, where research process decisions affect potential candidate value, further incorporate simple estimation of how the candidate value varies based on the target product profile. Factors such as ease of dosing in this profile can then be causally linked to the relevant predictors within the research process (e.g., bioavailability), to model the value of the predictive methods that might be used and to perform sensitivity analysis of how R D process choices affect the expected added... 

Factors affecting carotenoid bioavailability food sources and intakes... 

The bioaccessibility of a compound can be defined as the result of complex processes occurring in the lumen of the gut to transfer the compound from a non-digested form into a potentially absorbable form. For carotenoids, these different processes include the disruption of the food matrix, the disruption of molecular linkage, the uptake in lipid droplets, and finally the formation and uptake in micelles. Thus, the bioaccessibility of carotenoids and other lipophilic pigments from foods can be characterized by the efficiency of their incorporation into the micellar fraction in the gut. The fate of a compound from its presence in food to its absorbable form is affected by many factors that must be known in order to understand and predict the efficiency of a compound s bioaccessibility and bioavailability from a certain meal. ... 

A number of factors described as influencing carotenoid bioavailability were regrouped under the SLAMENGFll mnemonic. Species of carotenoid. Linkages at molecular level. Amount of carotenoids consumed in a meal. Matrix in which the carotenoid is incorporated. Effectors of absorption and bioconversion. Nutrient status of the host. Genetic factors. Host-related factors, and Interactions among these variables. Only the factors that affect the micellarization of the compound in the gut are discussed and summarized in Table 3.2.1. 

The degree of linkage of a compound may also affect its bioaccessibility in the gut. It is generally admitted that a compound linked with other molecules (e.g., via esterification, glycosylation, etc.) is not absorbed as well as its free form and thus it must be hydrolyzed in the gut in order to be taken up by enterocytes. Due to the presence of hydroxyl or keto groups on their molecules, the xanthophylls (lutein, zeaxanthin, and P-cryptoxanthin) are found in both free and esterified (monoester or diester) forms in nature, but few studies have been conducted to date to assess the bioavailabilities of these esters. 

As for PAHs, attempts have been made to increase bioavailability by use of surfactants, and a complex picture has again developed (Fava and Di Gioia 1998). Triton-100 exerted both positive and negative effects in soil slurries even though it was not metabolized by the soil microflora, it adversely affected the degradation of chlorobenzoate intermediates, whereas in fixed-bed reactors, depletion of PCBs was enhanced. 

Compound solubility is important because it affects the bioavailability of compounds in vivo, the behavior of compounds in in vitro assays, and the ease with which preclinical in vivo studies can be run. Solubility assays that measure either... 

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

Delay in absorption by food Yes No reports of increased rate of absorption with fatty meals (extended-release capsule) Unknown Yes food slows the rate of absorption but not the extent for DVPX Bioavailability not affected by food... 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

Another physical property that can affect the appearance, bioavailability, and chemical stability of pharmaceuticals is degree of crystallinity. Amorphous materials tend to be more hygroscopic than their crystalline counterparts. Also, there is a substantial body of evidence that indicates that the amorphous forms of drugs are less stable than their crystalline counterparts [62]. It has been reported, for example,... 

A good deal of attention recently has been directed towards the use of derivatives of cyclodextrin for the solubilization and stabilization of pharmaceuticals [124 126]. One cautionary note—complexation may adversely affect the dissolution an/or permeability characteristics of the drug, thereby possibly decreasing drug bioavailability. 

The bioavailability of drugs from tablets can be markedly influenced by the rate and efficiency of the initial disintegration and dissolution process. Unfortunately, one is faced with a compromise situation — a structure that has both a durable structure prior to administration and the ability to readily break down when placed in the in vivo environment. One of the major factors affecting both these properties is the structure of the tablet, in particular its density (or porosity) and the pore structure. Study of the significance of such measurements and interpretation of the results is a relatively recent field of interest. 

The physical characteristics should be considered (in combination as appropriate) in relation to the proposed dosage form and route of administration. Factors to be considered extend to solubility characteristics, crystal form and properties, moisture or solvent content, particle size and size distribution (which may affect bioavailability, content uniformity, suspension properties, stability, and preclinical or clinical acceptability), polymorphism, etc. 

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