Fraction of drug absorbed

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

The fraction of drug absorbed, F, represents the ratio of AUC of drug from a dosage form to the AUC of the same drug from a readily available preparation such as an intravenous injection where the drug is administered directly in the blood stream. This may be expressed as follows ... 

To obtain an average plasma concentration of 25 ng/mL with a dosing interval of 8 hours, what should be the dose of the drug when the fraction of drug absorbed is 0.8 It is known that the drug has a volume of distribution of 75 L and has an elimination rate constant of 0.173 hour1. 

If the fraction of drug absorbed is 0.9, dose is 25 mg, dosing interval is 6 hours, volume of distribution is 20 L and the average plasma concentration is 25 mcg/mL, what is the plasma half-life of the drug ... 

A key assumption of this steady-state model is that complete transfer of drug occurs from the lumen to the portal vein (i.e. mass of drug loss reflects mass of drug appearing in blood). Therefore, the fraction of drug absorbed (/a) can be thus defined as per Eqs. 2.20 and 2.21 ... 

Figure 5.2 Literature data on fraction of drugs absorbed (in percent) after human nasal administration versus apparent permeability (Tapp) data from Ussing chamber studies on porcine nasal mucosa (Reprinted with permission from Elsevier B.V.).

Presystemic elimination refers to the fraction of drug absorbed that is excluded from the general circulation by biotransformation or by first-pass binding. 

Whereas some transporters located in the apical wall of the enterocyte facilitate absorption, there are others that serve as efflux transporters. These are considered as the multiple drug resistance (MDR) transporters, and they play a major role in the disposition of many drugs. The most extensively studied MDR transporter is the apical P-glycoprotein (P-gp) efflux pump that reduces the fraction of drug absorbed by transporting the drug from the enterocyte back to the intestinal lumen [6]. 

Recently, certain lipids and surfactants have been shown to reduce the activity of efflux transporters in the GI wall, and hence, to increase the fraction of drug absorbed. Because of the interplay between P-gp and CYP3A4 activity this mechanism may reduce intraen-terocyte metabolism as well. This issue will be further explained in detail separately (Section 6.3.2.2). 

Ointments are semisolid preparations intended for topical application. They are used to provide protective and emollient effects on the skin or carry medicaments for treating certain topical ailments. They are also used to deliver drugs into eye, nose, vagina, and rectum. Ointments intended for ophthalmic purposes are required to be sterile. When applied to the eyes, they reside in the conjunctival sac for prolonged periods compared to solutions and suspensions and improve the fraction of drug absorbed across ocular tissues. Ophthalmic ointments are preferred for nighttime applications as they spread over the entire corneal and conjunctival surface and cause blurred vision. 

Figure 3.2. It can be seen that for high An, the critical range of the dose number and the dissolution number is around 1, where sharp changes in the fraction of drug absorbed are obtained due to small changes in D0 and Dn [6].

Generally, a plot of the fraction of drug absorbed (FJ against the fraction drug dissolved (Fd) is made wherein the fraction absorbed is obtained by deconvoluting the plasma profile. Often the goal is to develop a profile that need not a priori be a linear or even a predefined function. For example. 

Note that the precision values depend on the likely range of plausible parameter values. For CL and Vd, the precision is set lower than for Ka since the value of the fraction of drug absorbed (F), which scales both parameters, may inflate the apparent values signiflcantly. If f were known to be close to 1, then higher values... 

FIGURE 46.1 Level A correlation showing the point-to-point relationship between the fraction of drug absorbed and the fraction of drug dissolved. 

Obtain the absorption-time profile for these formulations (fraction of drug absorbed versus time). This can be achieved by the use of appropriate deconvolution techniques. 

The most commonly used model-dependent deconvolution methods for estimating the apparent in vivo drug absorption following oral administration are the Wagner-Nelson (5) method and the Loo-Riegelman method (6). These methods depend on mass balance and the fraction of drug absorbed for a one-compartment model is expressed as... 

FIGURE 46.11 Relationship between fraction of drug absorbed and fraction dissolved. FRD is fraction of drug dissolved, and FRA is fraction of drug absorbed. 

The fraction of drug absorbed into the systemic circulation after extravascular administration is defined as its bioavailability. 

Fgut is the fraction of drug absorbed into the enterocytes that escapes presystemic intestinal elimination. It is the fraction delivered into the portal vein after gut first pass. Compounds with significant gut first pass tend to have high exposure variability since the enzymes or transporters responsible for the first pass could be induced, inhibited, or saturated at different extent among individuals [11], Therefore, this undesired property should be screened out in the lead optimization stage. 

Figure 4.3 Simulations of fraction of drug absorbed after oral administration for a high-permeability drug (Peff = 4.5 x 10"4 cm/s) for doses 1-100 mg, water solubilities 0.1-10 g/mL and radius of drug particles 0.6-60 pm During variations of one variable, the others are held constant at the midpoint level (dose 10 mg, solubility 1 pg/mL and particle radius 6 pm).

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