Bioavailability plasma drug concentrations

Bioavailability is the amount of drug in a formulation that is released and becomes available for absorption or the amount of the drug absorbed after oral administration compared to the amount absorbed after intravenous administration (bioavailability - 100%), judged from areas remaining under plasma drug concentration-time curves. 

In the case of metoprolol succinate and metoprolol fumarate, the maximum drug concentration in the plasma( max) and the area under the plasma drug concentration-time curve were statistically equivalent, based on a 90% conLdence interval (Sandberg et al., 1993). With fenoprdffcQmthe following administration of its calcium salt was reached somewhat later thaCmjpassociated with the sodium form (Rubin et al., 1971). This was attributed to the slower dissolution rate for the calcium salt in acidic pH. Bioavailability and the measured distribution and elimination parameters, however, were reported to be similar. 

Fluctuation of plasma drug concentration is an important aspect of the bioavailability of slow-release formulations, which almost always have lower Cmax values for a standard dose size than, albeit similar AUC to, a more rapidly absorbed tablet. Assuming that the assay can handle the inevitably lower plasma concentrations, a useful measure of fluctuation, after the initial absorption phase of the curve and during the next four half-lives of elimination, is ... 

If the clearance is plasma drug concentration-dependent, and either intravenous exposure is limited by blood stream solubility or the drug has very low bioavailability, there could be an error in the estimation of absolute bioavailability. For more on these PK parameters, see Chapter 3. Additionally, extravascular and intravenous administrations are performed at two different time periods any changes of metabolism in the study subject may also affect the calculated absolute bioavailability. 

In these studies, standard bioavailability variables such as the extent of bioavailability determined from area under the curve (AUC), rate of bioavailability related to peak plasma drug levels (Cmax) and time to peak (fmax) are determined. A more detailed presentation of the assumptions and interpretations of bioavailability data is given in Chapter 7. The bioavailability after administration in more distal parts of the intestine, such as the terminal ileum and different parts of the colon, is compared with a reference administration either as an oral solution or as a regional delivery to the upper small intestine. This is exemplified in Figure 4.18, which shows the plasma drug concentrations of metoprolol after administration to jejunum, terminal ileum and colon ascendens or transversum. 

Direct Measures of Bioavailability Based on Plasma Drug Concentrations... 

The peak plasma drug concentration (units = ag/ml or ng/ml, etc.) The Cniax is also a measure of the extent of bioavailability or peak exposure and indicates concentrations required for a therapeutic or toxic response. It relates to peak exposure of the drug. is obtained directly from the plasma concentration time profile. 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

Ribavirin can be administered as an aerosol using a small-particle aerosol generator. When administered by this route, the drug has only minimal systemic absorption, with drug concentrations in respiratory tract secretions approximately 100 times as high as those found in plasma. Oral absorption is rapid, and first-pass metabolism is extensive ribavirin s oral bioavailability is 64% and can be increased by administration with a high-fat meal. Steady-state levels are reached after 4 weeks. 

Although itraconazole and fluconazole are both triazoles, they are chemically and pharmacologically distinct. Itraconazole (Sporanox) is lipophilic and water insoluble and requires a low gastric pH for absorption. Oral bioavailability is variable, only 50 to 60% when taken with food and 20% or less when the drug is taken on an empty stomach. Itraconazole is highly protein bound (99%) and is metabolized in the liver and excreted into the bile. With initial dosing, the plasma half-life is 15 to 20 hours steady-state serum concentrations are reached only after 2 weeks of therapy, when the half-life is extended to 30 to 35 hours. In lipophilic tissues, drug concentration is 2 to 20 times that found in... 

Bioavailability refers to the portion of a drug absorbed from the site of administration. The reference site of administration is intravenous, because this route produces 100% absorption. Figure 3-1 illustrates three sample drug concentration curves in plasma as a function of time. The area under the curve (AUC) is the total amount of drug in the systemic circulation available for distribution to the sites of action. The same dose completely absorbed from any of these routes would produce an identical area under the curve (i.e., 100% bioavailability), although the shape would differ. 

Chronic alcohol ingestion can cause cirrhosis, reducing hepatic CYP enzyme concentration and liver mass, and causing portacaval shunting. These effects will result in increased plasma drug levels due to both greater bioavailability (due to reduced first pass metabolism) and due to decreased clearance. Thus, dose adjustment is necessary and should be guided by TDM when possible. 

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