Biopharmaceutics. Группа авторов

that survives the gut‐wall metabolism then passes through the liver via the hepatic portal vein (Figure 2.4) where it gets metabolized, also referred to as the ‘first‐pass effect’; some drugs are subjected to a significant first‐pass metabolism by the liver. The drug can also be metabolised by various other tissues during its distribution in the body. Some drugs are also subjected to hepatobiliary excretion, where a fraction of the absorbed drug is excreted back into the small intestine through the bile, which either gets reabsorbed or excreted via faeces.

      The liver is responsible for most of the metabolism of the drug circulating in the body, irrespective of the route of administration. The drug metabolism in the liver mainly encompasses Phase‐I chemical reactions to make minor structural changes, for instance, oxidation, reduction or hydrolysis, that helps in excretion of the drug through the kidneys. Some drugs also undergo a Phase‐II (conjugation) reactions, where the drug is coupled with large biomolecules, such as glucuronic acid, glutathione or amino acids. These conjugated drugs are then eliminated in the urine by the kidneys.

      The degree of drug metabolism can be affected by the liver function of the individual. Damage to the liver can reduce the metabolic capacity of the liver resulting in increased bioavailability of certain drugs. The hepatic enzymes can also be inhibited by some co‐administered drugs and a potential interaction between two drugs may also lead to an increased drug fraction escaping metabolism, therefore, may require dosage adjustments. Conversely, certain foods or co‐administered drugs can also act as enzyme inducers and can lead to an increased hepatic clearance of the drug and may reduce the bioavailability of certain drugs.

      2.7.2 Excretion

Most of the drug (unchanged and its metabolites), along with other metabolic wastes that are produced in the body as part of the daily routine, are excreted in urine via the kidneys. Renal excretion, therefore, is considered as the prime route of elimination for many drugs. The kidney receives about a quarter of the cardiac output; ~1.25 L blood flows through kidneys every minute. The renal tubule is the unit structure in the kidney that is responsible for filtering the drug, metabolites and other wastes, and is also referred to as nephron. There are hundreds of thousands of nephrons present in each kidney. The drug and metabolites along with other waste products are filtered at the glomerulus that is a bunch of blood capillaries twisted into Bowman’s capsule in each nephron (Figure 2.7).

The drug and its metabolites are chiefly filtered passively at the glomerulus. The plasma flow to the glomerulus is ~120 mL/min, also known as the Glomerulus filtration rate (GFR). The drugs and metabolites that cannot be passively filtered (ionised, large molecular structure, conjugates, etc.) rely on transport proteins to actively secrete these molecules in the proximal tubule by a process known as the active tubular secretion (ATS), for example, penicillins. Often unionised drugs (permeable) are reabsorbed back into the body from the distal tubule. The changes in urine pH (acidification or alkalinisation) can therefore affect the urinary excretion of many ionisable (acidic or basic drugs), such as aspirin.

Figure 2.7 An illustration of the renal tubule (nephron) and its cortex and the medullary regions. CD, collecting duct; DCT, distal convoluted tubule; PCT, proximal convoluted tubule; PST, proximal straight tubule and TAL, thick ascending limb.

       Source: From Kumaran and Hanukoglu [1] / John Wiley & Sons / CC BY 4.0.

      The rate and extent of drug elimination by the body are therefore significantly affected by the renal function. The renal function is related to age, sex, body weight, hydration state, pregnancy, oedema, altered protein binding and other factors. The renal function can also be compromised by co‐administered drugs or toxins or due to a pre‐existing pathological condition, such as chronic kidney disease. The dosages for drugs that are chiefly cleared by the kidney are, therefore, adjusted according to the patient's renal function. The renal function in a patient can be estimated by the creatinine clearance.

Creatinine is an endogenous waste produced as a result of muscle metabolism, that is filtered at the glomerulus and eliminated via the urine. Normal creatinine clearance can, therefore, indicate a healthy renal function. If renal function is compromised, renal excretion of creatinine is reduced and the accumulation of creatinine results in increased serum concentration of creatinine. Creatinine clearance can be accurately measured in a patient by measuring the serum concentration of creatinine (requires a blood sample) and a 24‐hour urine collection to measure creatinine excretion rate in the urine. The creatinine clearance can also be estimated in a patient using Cockcroft and Gault method (refer British National Formulary) which only requires a single‐point serum creatinine concentration and uses patients body weight and age to estimate the creatinine clearance, and therefore is quicker and easier method for the routine clinical practice. However, this method is subject to significant estimation errors in either subjects with a very lean muscle mass (very low body mass index) or morbidly obese individuals, therefore, requires a careful clinical interpretation.

2.8 Elimination Half‐Life (t_½)

      Elimination half‐life is denoted as t_½ and reported in a unit of time (such as minutes or hours). It is an important pharmacokinetic parameter that helps to understand the rate of drug elimination from the body. Half‐life can be defined as ‘the time it takes for the plasma (or blood or serum) drug concentration to reduce by half’. Drug elimination from the body is non‐linear and follows first‐order kinetics for most drugs; therefore, the elimination phase of the pharmacokinetic curve can be explained by the drug's half‐life. Half‐life is a concentration‐independent property; therefore, it can be determined at any point in the elimination phase of the plasma drug concentration–time profile.

Figure 2.8 shows a first‐order pharmacokinetic profile following intravenous drug administration on a log‐linear scale. The profile shows that the drug concentration reduces to half every two hours; hence, the drug's elimination half‐life (t_½) is two hours.

      Half‐life, can be used to calculate how long it will take for a drug to be completely removed from the body following a dose, often referred to as the washout period. Typically, it takes three to five half‐lives for most of the drug to be eliminated from the body.

This would mean that a drug with t_½ = 2 h will take about 6 to 10 hours to eliminate from the body (Box 2.4). The drug concentration in the body after five half‐lives does not reach a mathematical zero but is so little that five half‐lives principle is usually acceptable in pharmacokinetic studies. The wash‐out period is important in clinical research and drug development to plan studies and to generate the cleanest possible data set.

2.9 Elimination Rate Constant

The elimination rate constant (k) (also written as k_e or k_el) represents the proportion of the drug in the body that is eliminated in a given time. The k is expressed as the inverse of time, for example, h⁻¹ or min⁻¹. For instance, a drug with k = 0.1 h⁻¹ will mean that 10% of the drug is being eliminated out of the body each hour. The elimination rate constant is closely related to the elimination half‐life and it complements the understanding of drug elimination. The elimination rate constant of a drug can be calculated