Drug: Distribution and Excretion | Pharmacokinetics

After reading this article you will learn about:- 1. Factors Affecting Blood Concentration of a Drug 2. Absorption of Drug 3. Distribution 4. Dosage Forms 5. Nome nclature 6. Bioavailability 7. Apparent Volume of Distribution (VP) 8. Excretion.

Factors Affecting Blood Concentration of a Drug:

The following factors can affect the blood concentrations of a drug: 

(i) The route of drug administration.

(ii) The dose of a drug.

(iii) One product may differ in bioavailability from the same dose in a second product.

Pharmacokinetics can describe the bioavailability differences among drug and drug products in an animal of same species or animals of different species. The job of veterinary clinicians is a little bit difficult owing to species variation. There is unfortunately no equivalents in the rate of elimination of the same substance by different species of animals.

Absorption of Drug:

For producing a systemic effect the drug must be absorbed and reach at the site of action in appropriate concentration. Drug absorption is defined as a process by which it enters into blood circulation. Drugs are generally given by oral or parenteral route when a systemic effect is desired.

Absorption from i.m and s.c. Injections:

Drugs given by parenteral route, bypass gastrointestinal tract. The absorption by these routes is rapid. After an aqueous solution, the drug given either by i.m. or s.c., achieves its peak within 30 minutes post administration.

(a) Factors Affecting Drug Absorption through i.m. and s.c.:

(i) Blood flow to the injection site.

(ii) Dose administration or concentration of the drug at the site of administration.

(iii) Lipid solubility of a drug.

(iv) Extent of ionization and un-ionization.

(v) Area of absorption surface.

(vi) Drug interaction.

(vii) Formulations (e.g., sustained-release preparations).

Percutaneous Absorption:

Factors governing absorption through skin depends on:

(i) Dissolution and release of drugs.

(ii) Power of penetration of keratin layer.

(iii) Lipid solubility.

(iv) Base included in preparation.

I.V. Injection:

Drug directly reaches in blood circulation and one can predict its plasma concentration. The onset of drug effect through this route is quick. This route is preferred over other routes especially in emergent disease conditions or when a high drug concentration of a particular drug is quickly required.

Clinicians have their own control over the dose to be administered especially while inducing surgical anesthesia with pentobarbital in dogs and small ruminants where the exact dose is not pre-calculated but the amount to be administrated is determined by the response of the animal. The plasma concentration of a drug is initially higher as compared to other routes of drug administration at the similar dosage (Fig. 2.5).

Drug Absorption by Oral Route:

(a) Events of Absorption:

(i) Drug release from dosage forms.

(ii) Transport across GI mucosal barrier.

(iii) Passage through the liver.

Dissolution:

Drug release from solid dosage forms is called dissolution. It is the major factor that regulates drug absorption after oral administration. Following the drug release, the lipid soluble drugs diffuse through the mucosal barrier to enter the hepatic portal venous blood. Acid stable drugs are well absorbed from the GI tract.

Hydrochloride salts are incompletely absorbed however, some of them must not be given in a fasting animal especially dogs, because of their tendency to cause GI disturbances.

The small intestine is the principal site of absorption for all drugs given orally regardless of their physicochemical properties, owing to the large volume of ruminal fluid, a drug can attain only a low concentration in this organ, no matter whether it is given in solid or liquid dosage form.

(a) Facts to be Remembered:

(i) Non-ionized weak organic acids are well absorbed from the rumen.

(ii) Chronic oral dosage of an antibiotic can suppress the microflora activity and can produce anorexia.

(iii) Lipid soluble bases, given parenterally diffuse from the systemic circulation into ruminal fluid and are trapped by ionization depending on their pka value (ion-trapping).

(iv) Acids exist mainly non-ionized at pH below the pka. Acids are non-ionized in acidic media and bases in acidic media are more ionized.

Factors Affecting Absorption (oral route):

(i) Particle Size of a Drug:

If the particles size of a drug is smaller it is readily absorbed from the site of administration. The tablets having larger aggregates do not dis-integrate easily and their absorption is slow.

(ii) Solubility and Extent of Ionization:

Un-ionized drugs are more lipid soluble and are absorbed readily than the ionized drugs which are comparatively less soluble. If the pH of medium is acidic, weak organic acids are ionized to a lesser extent, more un-ionized and readily absorbed.

For an example acidic drugs are more absorbed from the stomach of the dog. Similarly weak bases are more un-ionized at alkaline pH. The pH of intestine is alkaline, therefore, basic drugs are absorbed quickly from intestine.

(iii) Area of Absorption Surface:

If the absorption area is larger, the absorption is greater e.g., the area of small intestine is more, absorption is comparatively greater in this part.

(iv) Physical State of Drug:

Liquids are absorbed better than solids. Larger tablets are better absorbed than smaller tablets.

(v) Functional State of the GI Tract:

Gastrointestinal disorder can impair the drug absorption process. For example, increased peristalsis during diarrhoea reduces the drug absorption.

(vi) Food Particles:

Presence of food in stomach retards the absorption of the drug and therefore, many of them are given in empty stomach. However, drugs that cause irritation in empty stomach should be given after meal. Tetracycline is not administered orally after drinking milk because it forms a complex with calcium of milk thus the absorption is reduced.

Distribution of Drugs:

After a drug is absorbed, it is distributed to various organs and body fluids. If the drug will not be distributed after its absorption it will not reach at the site of action and thus, it will be of no use for systemic infection.

The rate, pattern and extent of distribution are governed by:

(i) Physico-chemical property of a drug,

(ii) Cardiac output.

(iii) Regional blood flow.

(iv) Plasma protein binding.

(v) pH and solubility of drug.

(vi) Active transport.

Plasma Protein Binding:

Plasma contain primarily albumins and globulins. Most of the drugs reaching into the circulation binds to the albumin (MW 69, 000). For example, salicylates, phynylbutazone and penicillins (weak acids) are highly bound to albumin.

However, the strength of the drug binding to albumin is different for each drug. Weak basic drugs such as propanolol, lidocain, procainamide, neostigmine, trimethoprim (weak bases) bind particularly to α₁ – acid glycoprotein. Such bindings of drugs with other proteins is much small.

Plasma protein binding is an advantage because it acts as reservoir. When plasma drug concentration falls, the reservoir releases the drug in free form. The plasma protein bound drug is inactive where as the free drug is pharmacologically active.

However, the plasma protein bound drug is of large molecular weight and does not filter through glomerulus and thus increases the duration of action. The total drug in the plasma that is bound is determined by the concentration, its affinity to the binding sites and total number of binding sites.

Plasma protein binding for most of the drug is a reversible process. Reversible plasma protein binding implies that the drug binds the protein with weaker chemical bonds such as hydrogen bonds or van der waal forces. Simple mass equation describes the free and bound concentrations.

At low concentration of drugs the fraction bound is a function of the concentration constant. At high drug concentrations, the fraction bound is a function of the number of binding sites and the drug concentration. The binding values of some chemotherapeutics are given in Table 2.1.

The plasma protein binding of a drug limits its concentration in tissue and at the site of action, because it is unbound drug which can cross the membrane. Many drugs compete each other for protein binding sites.

In this situation, it is dangerous condition when a given drug is displaced and has a limited volume of distribution. If the competition extends to the drug bound in tissues, elimination of drug is also reduced if the displacing drug is given in a high dosage by i.v. injection.

There are many reservoirs like fat, bone and trans-cellular reservoirs. Protein binding for some of the drug is an irreversible process which is usually a result of chemical activation of the drug which then attaches strongly to the protein by covalent chemical bonding.

Such type of bonding occurs for certain type of drug toxicity which can occur over a long time period as in the case of chemical carcinogenesis or within a relative short time period as in the case of drug that form reactive chemical intermediates. For example, the hepatotoxicity of high doses of acetaminophen is due to the formation of reactive metabolites intermediate which interacts with liver proteins.

Factors Affecting Protein Binding:

(i) The drug (pka value and its concentration)

(ii) The quantity of protein available for binding.

(iii) The affinity between drug and protein.

(iv) Drug interaction (poly-therapy).

(v) Disease conditions.

Dosage Forms of Drugs:

Preparations of drugs that provide convenient means of administration of a dose to the patients are known as dosage forms.

(i) Solid dosage forms: powder, compressed tablets, capsules, bolus etc.

(ii) Liquid dosage forms: mixtures, emulsions, syrup, elixirs etc.

(iii) Repository dosage forms: implants and pellets.

(iv) External dosage forms: iniments, lotions, ointments, creams, dusting powders and aerosols.

Nomenclature of Drugs:

Each drug has three names:

(i) Chemical:

It provides precise description of the drug based on chemistry. Chemical names are complex and cumbersome for clinicians.

(ii) International Non-Proprietary Name (INN):

These names are also known as generic name. The names of drugs which are written in books to describe their pharmacological activities are generally generic names.

(iii) Proprietary Names:

These names are given by the manufacturing company and are also known as brand name or trade names. The generic name of a drug may be called by different brand names and are written by clinicians in their prescription.

Bioavailability of Drugs:

The bioavailability of a drug is defined in terms of:

(i) The amount of administered drug which reaches the systemic circulation and

(ii) The rate at which that happens.

The rate of availability depends upon pharmaceutical factor and gastrointestinal absorption, metabolism being relatively unimportant on the other hand the extent of bioavailability depends on both the extent of absorption and the extent of metabolism.

First-Pass Effect (First-Pass Metabolism):

An important factor separate from absorption across the gut wall which is after determinant of bioavailability is the extent of metabolism occurring before the drug enters the systemic circulation.

The sites for first-pass metabolism are:

(i) The gut lumen

(ii) The gut wall

(iii) The liver

Physicochemical Aspects of Drug and Bioavailability:

Bioavailability is the term which is commonly used for the rate and amount of drug that reaches in the systemic circulation. It is the bioavailability that determines whether the drug is therapeutically effective or is toxic to the animal in which it has been administered. It is the physicochemical property of a drug that plays an immense role in governing the drug availability.

The word physicochemical is generally used to indicate whether the drug is a weak organic acid or base, what is the pH of the environment in which it has reached (i.e., pH of the stomach, intenstine, milk and urine). Because of the factors involved in drug availability, specially in GI absorption, drug levels after enteral administration are subject to more variation than are drug levels after parenteral administration.

Factors Affecting Bioavailability:

A drug which reaches the systemic circulation from the site of application or administration, has to pass through different rate processes (Fig 2.7).

The above processes are:

(i) Disintegration of drug product and subsequent release of the drug.

(ii) Dissolution of the drug in an aqueous environment.

(iii) Absorption across cell membranes into the systemic circulation.

Apparent Volume of Distribution (VP):

Apparent volume is defined as the apparent volume (Vd) in which the drug is dissolved. It is believed that the administered drug in the body is rapidly distributed throughout the body. However, each individual tissue may contain a different concentration of drug due to differences in the drug affinity for that tissue.

The value of a volume of distribution does not bear a true physiological meaning in terms of a anatomic space. Hence, the term apparent volume of distribution is used.

The amount of the drug in the body is not determined directly. Practically, a blood sample is removed at periodic intervals and analysed for its concentration of a drug. It is an important pharmacokinetic variable that relates the concentration of a drug in plasma and the amount of drug in the body.

In pharmacokinetic study, the body is considered as a constant volume system. Therefore, the apparent volume of distribution for a given drug is generally a constant. If both the concentration of a drug in plasma and the apparent volume of distribution for a drug are known, the total amount of the drug in the body (at the time when plasma sample was collected) can be calculated by:

D = Vd x Cp Eq. 2.3

Where, D = total drug; Vd= volume of distribution:

Cp = plasma drug concentration.

Vd can be calculated as:

C⁰_P is initial plasma drug concentration at zero time (t=0).

Significance of Apparent Volume of Distribution:

(i) Most drug have an Vd value smaller or equal to body mass.

(ii) Some of the drugs show an Vd value several times more than the actual body mass.

(iii) The Vd value is dependent on C⁰_P thus, small C⁰_P results in a large Vd and high C⁰_P in a small Vd.

(iv) A very small C⁰_P occurs if the drug is concentrated in peripheral tissue and organs.

Situations when a high Vd value of a drug is obtained:

(i) If the plasma protein binding value of a drug is very low.

(ii) If the drug remains in the extravascular tissues or less concentrated intravascularly.

Low Vd Value is obtained:

(i) If the plasma protein binding value is high.

(ii) If the drug remains in the vascular compartment of the body.

Excretion of Drugs:

Metabolism, storage and excretion are the three mechanisms by which drugs are removed from the animal’s body. Storage of drugs in fat depots, in the reticuloendothelial system, and in bone play significant role in removal of lipid soluble agents, colloidal substances, and heavy metals respectively.

There are many route of drug excretion i.e., renal excretion, saliva, tear, faeces, bile, intestine, sweat, lungs and the mammary excretion. Drugs are eliminated either unchanged or as metabolites or sometime, both. Excretory organs eliminate polar compounds more effectively than the drugs having high lipid solubility. Thus, lipid soluble drugs in the body are metabolized to polar compounds for their easy excretion.

Renal Excretion:

Water soluble drugs having low molecular weight (3000) are primarily excreted through this route.

This process includes the combination of the following processes:

(i) Glomerular filtration

(ii) Active tubular secretion

(iii) Tubular reabsorption.

(i) Glomerular Filtration:

It is an unidirectional process. Most smaller molecules (molecular weight 500), non-ionized and ionized drugs are excreted through this route. Drugs which are bound to protein are of high molecular weight and are not excreted by this route. The major driving force involved in glomerular filtration of a drug is the hydrolytic pressure within the glomerulus capillary.

Factors Affecting Glomercular Filtration:

(i) Blood supply to kidney.

(ii) Free drug concentration.

(iii) Percent of protein binding.

(iv) Molecular weight (size of the molecule)

(v) pH of blood.

(vi) pka of drug.

Glomercular filtration rate (GFR) is determined by using a drug which is neither reabsorbed nor secreted within the renal tubules. Inulin and creatinin are the best example used for measurement of glomerular filtration. Thus, the clearance of inulin will be equivalent of 125-130 ml/minute.

(ii) Active Tubular Secretion:

It is an active transport process which is carrier mediated and requires energy input. It is capacity limited and therefore, may be saturated. Drugs having a similar structure can compete for the same carrier system. For example probenecid is used to block the tubular secretion of penicillins because it competes with penicillin for the same carrier system.

As a result, it has been observed that administration of probencid with penicillins and some of the cephalosporins elivates their plasma concentrations and prolongs their plasma half-life.

This merit of probenecid may be employed by veterinary clinicians where a high plasma concentration of these antimicrobials are needed. On the other hand this can cut short the dosage of these antimicrobials and can minimise the cost of therapy.

Drugs which are commonly used to measure the active tubular secretion are -p -aminohippuric acid (PAH) and iodopyracet (Diodrast). These substances are filtered by glomerulus and are also secreted by the tubular cells. Active secretion for these drugs is very rapid and the amount which is carried to the kidney is eliminated in single pass.

The clearance of these drugs therefore, depends on the effective renal plasma flow (ERPF) which varies from 425-650 ml/minute. For a drug which is mainly excreted by glomerular filtration the plasma half-life may change markedly.

(iii) Tubular Reabsorption:

It may be active or passive and generally occurs after the drug is filtered through the glomerulus. The value for clearance of drugs are zero which are completely reabsorbed (e.g., glucose). The value for clearance is less than glomerular filtration rate especially for those drugs which are partially absorbed.

Factors Affecting Re-absorption:

(i) pH of urine.

(ii) pKa of drug.

(iii) Extent of ionization and non-ionization.

(iv) Diet rich in carbohydrates.

(v) Drug infraction.

(vi) Intravenous fluid administration.

The effect of urinary pH on reabsorption occurs with weak organic bases having pKa of 7.5-10.5. The concentration ratio for the distribution of weak organic acid or base between urine and plasma is derived by the following formula:

Biliary Excretion:

The mechanism of biliary excretion is poorly understood. Many substances appears in bile in concentration similar to that of plasma. A number of highly ionized organic acids are secreted into bile in very high concentration that suggest a presence of an active transport system analogous to one of the kidney. Boundary between the blood and the bile is a highly porous structure.

Enterohepatic Circulation:

From the kinetic stand point of view the enterohepatic circulation is very important. If a drug metabolite or drug itself is excreted in significant amount in the faeces, complete elucidation of the kinetics would require determination of whether the material in the faeces is partly or wholly unabsorbed drug, drug which comes from biliary excretion or from secretion through the intestinal wall.

Enterohepatic circulation is responsible for prolonged retention of certain drugs in animals body. Enterohepatic circulations may cause secondary peaks, shoulders or oscillation in blood concentration time curve.

If enterohepatic circulation is prominent, the compartment model should have a reversible transfer between the compartments representing blood and the absorption sites. For such models, the true rate constant for elimination can not be estimated from the terminal blood concentration data.

Many compounds excreted in bile enter small intestine e.g., tetracyclines, morphine, chloramphenicol etc. Many of the glucuronide conjugates are hydrolysed by β- glucuronidase and liberated compounds are reabsorbed. The cycle, consisting of biliary excretion followed by re-absorption is known as enterohepatic circulation.

Mammary Excretion:

Many of the weak organic acids and bases diffuse across the mammary gland membrane which is a benefit to clinicians in the treatment of mastitis in animals. Mammary gland epithelium is permeable to the non-ionized form of many sulphonamides, benzylpenicillins, erythromycin, penethamate; chloramphenicol; nitrofurantoin; ampicillin and mebendazole diffuse into milk due to non-ionic diffusion

Milk to plasma ultra filtrate ratios is compared to the theoretical ratios as per pH partition concept:

For weak acids:

For weak bases:

Factors affecting Milk-to-Plasma Ratio:

(i) Milk pH:

Small changes in milk pH markedly change the total drug concentration of drug having small pKa (e.g., salisylic acid, pKa-3.0). However, relatively large changes in pH does not change the concentration of organic acids with high pka values (sulphanilamide, pKa-10.4).

(ii) The bases with lower pKa values are less affected than the bases with high pKa values.

(iii) The un-ionized portion of the drug molecule passes across membrane.

(iv) Extent of ionization- Organic acids having low pKa values are ionized in the more alkaline milk and are trapped and show high level of milk concentration.

(v) Inflammation of the mammary gland.

Elimination Rate Constant:

The rate of elimination from the body for most of the drugs follows first order reaction process. The elimination rate constant, β, is a first order elimination rate constant. In general, only the parent drug is measured in the vascular system. The total elimination of drug from this compartment is affected by metabolism and excretion.

Thus, the elimination rate constant is the sum of metabolism and excretion and can be represented as:

There are several routes of drug excretion including metabolism and excretion. In such case the process has its own first order rate constant.

The above equation shows that the rate of elimination of a drug in the body is a first order process depending on the elimination rate constant, β, and the amount of drug, Dp, remaining.

Integration of equation 2.8 gives the following equation:

Where Dp is amount of drug at time t and C⁰_p is the drug in the body at zero time (t = 0). When log Dp is plotted against t for this equation a straight line is obtained. In practice instead of transforming values of Dp to their corresponding logarithms, each value of Dp is plotted at logarithms intervals on semi-log graph paper:

Equation 2.9 can be written as;