Ladme Scheme In Pharmacology

Figure 1.2 Relationship between the pharmacokinetic, link, and pharmacodynamic models.

Figure 1.2 Relationship between the pharmacokinetic, link, and pharmacodynamic models.

1.3 LADME Scheme and Meaning of Pharmacokinetic Parameters

The frequently used acronym LADME, which stands for liberation, absorption, distribution, metabolism, and excretion, broadly describes the various biopharmaceutical processes influencing the pharmacokinetics of a drug. Since each of aspect of LADME can influence the phar-macokinetics of a drug and ultimately the design of controlled release delivery devices, this section will review and explain the relationship between LADME processes and eight common pharmacokinetic parameters (F, K ^ ix^ C1, km tmax, Cp,max).

Each of the LADME processes can have an impact on a drug's pharma-cokinetics profile, some more than others depending on the physicochem-ical properties of the drug, dosage formulation, route of administration, rates of distribution, patient's specific anatomy/physiology, biotransformation/metabolism, and excretion. From a pharmacoki-netics perspective, liberation encompasses all kinetic aspects related to the liberation of drug from its dosage form into its active or desired form. For example, free drug released from a tablet or polymeric matrix in the gut would be liberation. Although liberation is first in the LADME scheme, it does not need to occur first. For example, ester pro-drug formulations can be designed to improve gut absorption by increasing lipophilicity. These ester formulations deliver the prodrug into the systemic circulation, where blood esterases or even chemical decomposition cleaves the ester into two fragments, a carboxcylic acid and an alcohol; the desired free drug can be liberated as either the carboxcylic acid or the alcohol depending on the chemical design. Liberation kinetics can be altered by other physicochemical properties, such as drug solubility, melting point of vehicle (suppository), drug dissolution, gastrointestinal pH, etc. Overall liberation kinetics are fairly well known because they generally can be estimated from in vitro experiments. The foundational principles governing the liberation of drug from delivery systems were laid by many, who rigorously applied the laws and principles of physics and physical chemistry to drug delivery

1.3.1 Maximum concentration, time to maximum concentration, and first-order absorption rate constant Cp,max, tmax, ka

Although liberation and absorption can overlap, absorption is much more difficult to model accurately and precisely in pharmacokinetics. A great deal of work in this area by Wagner-Nelson13-15 and Loo-Riegelman16,17 reflects the complexities of using pharmacokinetics and diffusion models to describe the rate of drug absorption. Since most drugs are delivered via the oral route, the gastrointestinal (GI) tract is described briefly. In the GI tract, the source of these complexities lies in the changing environmental conditions surrounding the drug and delivery modality as it moves along the GI tract. Most drugs experience a mix of zero- and first-order kinetic absorption; this mixing of zero- and first-order input results in nonlinearities between dose and Cp (see "Linear versus Nonlinear Pharmacokinetics"). A widely used simplification assumes that extravascular absorption (including the gut) is a first-order process with a rate constant ka or kev or kabs; practically, Cpmax and tmax are also used to characterize the kinetics of absorption. Cpmax (i.e., the maximal Cp) can be determined directly from a plot of Cp versus time; it is the maximum concentration achieved during the absorption phase. tmax is amount of time it takes for Cp max to be reached for a given dose [see Fig. 1.14; the equations for Cp max and tmaxare given in Eqs. (1.28) and (1.29)].

1.3.2 Bioavailability F

While pharmacokinetics describing the rate of absorption are quite complex owing to simultaneous kinetic mixing of passive diffusion and multiple active transporters (e.g., P-glycoprotein,18 amino acid19) and enzymes (cytochrome P450s20-23) pharmacokinetics describing the extent of absorption are well characterized and generally accepted, with area under the Cp curve (AUC) (Eq. 1.1) being the most widely used pharmacokinetics parameter to define extent of absorption. AUC is closely and sometimes incorrectly associated with bioavailability. AUC is a measure of extent of absorption, not rate of absorption; true bioavailability is made up of both extent and rate of absorption. The rate of absorption tends to be more important in acute-use medications (e.g., pain management), and the extent of absorption is a more important factor in chronic-use medications.24 Frequently, the unitless ratio pharmacokinetics parameter F will be used to represent absolute bioavailability under steady-state conditions or for medications of chronic use.

In Eq. (1.2), the e.v. and i.v. subscripts stand for extravascular and intravenous, respectively. F is a unitless ratio, 0 < F < 1, that compares the drug's availability given in a nonintravenous route compared with the availability obtained when the drug is given by the intravenous route. F is also known as the fraction of dose that reaches the systemic circulation (i.e., posthepatic circulation).

1.3.3 Volume of distribution Vd

Volume of distribution Vd has units of volume but is not an actual physiologically identifiable volume. The first common definition of Vd is that "it is the volume that it appears the drug is dissolved in." The second definition for Vd is that "it is the proportionality constant that links the amount of drug in the body to the concentration of drug measured in the blood." Clinically, in general, the larger Vd is, the greater is the extent of drug partitioning and the greater is the amount of drug being removed from the site of measurement. Most drugs have a Vd of between 3.5 and 1000 L; there are cases where Vd is greater than 20,000 L (as in some antimalarial drugs).

1.3.4 Clearance Cl

Systemic clearance Cl can be defined as the volume of blood/plasma completely cleared of drug per unit time. Systemic clearance is calculated by dividing the amount of drug reaching the systemic circulation by the resulting AUC (Eq. 1.3). At any given Cp, the amount of drug lost per unit time can be determined easily by multiplying Cl x Cp.

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