Biopharmaceutics. Группа авторов

tissues through the blood circulation. Therefore, measuring drug concentration in blood gives a reflection of the drug concentration in various body tissues. A blood sample can be more easily obtained from a human volunteer or the patients as compared to the other body tissues. Blood is a complex matrix containing various cellular components (blood cells) and dissolved constituents in the liquid part of the blood. Refer to the schematic in Figure 2.5 to understand how plasma and serum differ from the whole blood.

Typically, when a drug concentration is measured in a whole blood sample, the concentration may not be the same as if measured in serum, or plasma. This is due to the changes in the volume that occur when plasma or serum is separated from the blood as well as potential binding of the drug to blood components, refer the illustration in Box 2.1 for an example to understand this phenomenon.

      Often, drugs have a tendency to bind to plasma proteins (like albumin) or the red blood cells (RBCs); in this case, it is necessary to differentiate between the ‘fraction bound’ and the free fraction of drug that is present. The drug concentration measured in plasma or serum may, therefore, specifically refer to the ‘fraction unbound’ of the drug and will not be the same as the total drug concentration in the whole blood. The ‘fraction unbound’ is also termed the ‘free fraction’ of the drug. It is this free fraction that is distributed to the body tissues, exerts its pharmacological effects and is also excreted via urine. The ‘fraction bound’ is usually confined to the blood circulation, is not distributed to the tissues and is often ‘unavailable’ for elimination via the kidneys. The ‘fraction bound’ and ‘fraction unbound’ are maintained in equilibrium, and the fraction bound becomes unbound with time due to a continuous reduction of the unbound fraction following drug elimination.

Figure 2.5 Illustration explaining how plasma and serum differ from blood.

Box 2.1 Drug Concentration in blood is not the same as the drug concentration in plasma!

      A drug concentration in a whole blood was measured as 1 mg/L. If the plasma was then separated from the whole blood, then the 1 mg of the drug that was present in the whole blood will now be present in the plasma provided that the drug does not bind to the RBCs (red blood cells).

      In a typical healthy male, plasma represents ~55% of the total blood volume. This will mean that the 1 mg of the drug will now be present in 0.55 L of the plasma instead of 1 L of the whole blood.

      This represents a plasma concentration of 1.8 mg/L, which is higher than the 1 mg/L – the concentration measured in the whole blood sample.

      Box 2.2 Why measure drug concentrations?

      The intensity of pharmacological effect (or toxic effect) is often related to drug concentration at the receptor site (in tissue). Measuring plasma drug concentration may help to adjust the dose to optimise the drug response or prevent serious toxic effects in an individual patient.

      Measuring drug concentration in blood during bioequivalence studies also helps to establish therapeutic equivalences between two different products of a drug (such as brand vs. generic) or different formulations of a drug (such as tablet vs. capsule).

The fraction bound can also be subject to a potential drug interaction; if a co‐administered drug had a higher affinity for the binding site at the plasma protein or the RBC, it could displace the other drug. This may result in a significant increase in the free fraction of a drug which can result in increased therapeutic effect (or toxicity) and increased elimination.

      The potency of drug response (the pharmacological or toxic effect) depends on the drug concentration at the target site in the tissues; measuring drug concentration in the blood (or in serum or plasma) helps to estimate the intensity of the drug response at a given dose.

2.6 Volume of Distribution

The volume of distribution (V) of a drug is a pharmacokinetic term that represents the hypothetical volume of total body tissues where a drug is distributed following administration. It is denoted in appropriate units of volume, usually litres (L) or litres per kilogram body weight (L/kg). Water represents most of the body weight, with total body water estimated approximately 42 L in a 70 kg healthy male that accounts for the 60% of the total body weight (Box 2.3). The total body water is represented by the blood volume (~5 L), the interstitial fluids (~11 L) and the intracellular fluids (~28 L).

Box 2.3 Total body water.

      1 Plasma: ~3 L (~4% body weight)

      2 Interstitial fluids: ~11 L (~16% body weight)

      3 Extracellular fluids (ECF) ~20% body weight

      4 Intracellular fluids: ~28 L (~40% body weight)

      5 Total body water, ~42 L ~60% body weight

      Based on an average 70 kg healthy male.

      A drug with a very low volume of distribution may mean that the drug is mainly distributed to the extracellular fluids, like blood and/or interstitial fluids.

The rate and extent of drug distribution into the body tissues is an interplay between physicochemical properties of the drug (e.g., molecular weight, solubility, lipophilicity, ionisation constant and partition coefficient) and its interaction with biomolecules (e.g., ability to bind to the blood cells or the plasma proteins). The rate and extent of drug distribution to a particular organ or a tissue also depends on the blood flow. The heart pumps about five litres of blood every minute (the cardiac output) of which about 30% passes through the liver, ~25% to the kidneys and about 14% to the brain. The drug is usually distributed to the highly perfused organs first (such as brain, heart, lung, kidney and liver) before it is distributed to other tissues with poor blood flow (Figure 2.6). In pharmacokinetics, a very large volume of distribution suggests that the drug is distributed deeper down the body tissues, for instance, the muscles and the adipose tissue.

2.7 Elimination

The drug is removed out of the body through metabolism and direct elimination via excretion. The process is often referred to as clearance in pharmacokinetics. The metabolism involves structural changes by biotransformation of the drug into different chemical entities, usually referred to as metabolites which can still be pharmacologically active (produce a therapeutic effect or are responsible for adverse reactions). These metabolites along with the unmetabolized drug are then subjected to excretion via the kidneys.

Figure 2.6 A typical drug distribution into the body following an intravenous dose.

      2.7.1 Metabolism

      Drugs absorbed from the gastrointestinal tract can undergo gut‐wall metabolism by various mucosal enzymes expressed in the