ADME Process

Drug ADME process
By: Tsegaye N. (B. Pharma., MSc)

Drug ADME process
 ADME describes disposition of a drug within a body.
 These processes influence the drug levels and kinetics of drug exposure to the
tissues; and hence influence performance and pharmacological activity of the
drug.
06/06/2024 Clinical PKs 2

Drug Absorption PKs
 Absorption is the transfer of unchanged drug from its site of administration to the
blood stream.
 Most drugs are absorbed by passive diffusion across a biologic barrier:
 Lipid diffusion
 Aqueous diffusion
 A few drugs are absorbed by active transport or by facilitated diffusion

 The rate of change in the amount of drug in the body, dDB/dt, is dependent on the
relative rates of drug absorption and elimination.
 Where DGI is amount of drug in the gastrointestinal tract and D E is amount of drug
eliminated.
 During the absorption phase of a plasma level–time curve, the rate of drug
absorption is greater than the rate of drug elimination.
 Note that during the absorption phase, elimination occurs whenever drug is
present in the plasma, even though absorption predominates
 When the drug at the absorption site becomes depleted, the rate of drug absorption approaches zero, or
dD GI/dt = 0.
 The plasma level–time curve (now the elimination phase) then represents only the elimination of drug
from the body, usually a first-order process.
 Therefore, during the elimination phase the rate of change in the amount of drug in the body is
described as a first-order process
ADME…
 Many pharmacokinetic studies are concerned principally with the bioavailability

of the drug.
 A drug that is absorbed slowly may not achieve sufficiently high concentrations at
the site of action to elicit a desired effect or intensity of effect, even if the entire
dose is absorbed.
 The extent of absorption is usually the more important factor for drugs that are
administered repetitively for the treatment of subchronic or chronic conditions

ADME…
 The average drug concentration in plasma at steady state during repetitive

administration is directly proportional to the
 Amount absorbed from each dose but is independent of the rate of absorption.
 For drugs administered extravascularly and intended to act systemically,
absorption is a prerequisite for pharmacological effects.
First-order Absorption
 First-order absorption means the absorption rate is proportional to amount of drug at
the absorption site.
 The fractional rate of decline is not constant for a first- order process.

ADME…
 The oral absorption of drugs often approximates first order kinetics, especially
when given in solution, IR, IM and SC drug delivery system
 In the case of a drug given orally, the dosage form first disintegrates if it is given
as a solid, then the drug dissolves into the fluids of the GI tract.
 Only drug in solution is absorbed into the body.
 The rate of disappearance of drug from the gastrointestinal tract is described by
 Where, k a is the first-order absorption rate constant from the GI tract, F is the fraction
absorbed, and D GI is the amount of drug in solution in the GI tract at any time t.

 Integration of the differential equation gives
 where D 0 is the dose of the drug.

 The rate of drug elimination is described by a first-order rate process for most
drugs and is equal to –kDB.
 The rate of drug change in the body, dDB/dt, is therefore the rate of drug in, minus
the rate of drug out—as given by the differential equation
 Where, F is the fraction of drug absorbed systemically.

 Since the drug in the gastrointestinal tract also follows a first-order absorption
across the gastrointestinal wall,
 The amount of drug in the gastrointestinal tract at any time t is equal to D 0e –kat .
 This equation can be integrated to give the general oral absorption equation for
calculation of the drug concentration (C p) in the plasma at any time t, as shown
below.

ADME…
Zero-order Absorption Process

 In zero-order absorption process, the fractional rate increases with time, because the
rate is constant but the amount remaining decreases.
 This can be achieved by a constant rate intra- venous infusion.
 It can also be approximated by some kinds of oral dosing.
 The rate of first-order elimination at any time is equal to DBk.
 The rate of input is simply k0.

 Therefore, the net change per unit time in the body can be expressed as
 Integration of this equation with substitution of VDCp for DB produces
 The rate of drug absorption is constant until the amount of drug in the gut, DGI, is
depleted.
 The time for complete drug absorption to occur is equal to DGI/k0.
 After this time, the drug is no longer available for absorption from the gut.
 The drug concentration in the plasma subsequently declines in accordance with a
first-order elimination rate process.
Drug Distribution PKs
 Distribution
 Is reversible transfer of a drug to and from the site of measurement (blood or
plasma).
 It is the passage of drug from the circulation to the tissue and site of its action.
 Volume of plasma in which the total amount of drug in the body would be required
to be dissolved in order to reflect the drug concentration attained in plasma.
 The extent of distribution of drug depends on its:
 Lipid solubility
 Ionization at physiological pH (dependent on pKa)
 Extent of binding to plasma and tissue proteins
 Differences in regional blood flow
ADME…
 Blood flow, tissue size, and tissue storage are also important in determining the
time it takes the drug to become fully distributed..
 Drug affinity for a tissue or organ refers to the partitioning and accumulation of
the drug in the tissue.
 The time for drug distribution is generally measured by the distribution half-life or
the time for 50% distribution.

 The factors that determine the distribution constant of a drug into an organ are
related to the blood flow to the organ, the volume of the organ, and the
partitioning of the drug into the organ tissue
 Where, k d = first-order distribution constant, Q = blood flow to the organ, V = volume of the
organ, R = ratio of drug concentration in the organ tissue to drug concentration in the blood
(venous).
 The distribution half-life of the drug to the tissue, t d1/2 may easily be determined
from the distribution constant, t d1/2 = 0.693/k d
 Vascular tissues such as the kidneys and adrenal glands achieve 95% distribution
in less than 2 minutes.
 In contrast, drug distribution time in fat tissues takes 4 hours, while less vascular
tissues, such as the skin and muscles, take between 2 and 4 hours.
 When drug partition of the tissues is the same, the distribution time is dependent only
on the tissue volume and its blood flow.
Volume of distribution
 The volume that would accommodate all the drugs in the body.
 A hypothetical volume that relates drug serum concentrations to the amount of drug
in the body.
 It has no direct physiological meaning; it is not a ‘real’ volume and is usually referred
to as the apparent volume of distribution.

 Where, DB is the amount of drug in the body, Vp is the plasma fluid volume, Vt is the
tissue volume, Cp is the plasma drug concentration, and Ct is the tissue drug
concentration.
 For many protein-bound drugs, the ratio of DB/Cp is
 Not constant over time,
 Depends on the nature of dissociation of the protein–drug complex and
 How the free drug is distributed; the ratio is best determined at steady state.
 It is important to realize that the Cp in plasma is not necessarily the same in the
liver, kidney or other tissues.
ADME…
 Thus, amount of drug in plasma does not equal amount of drug (X) in the kidney
or amount of drug (X) in the liver or amount of drug (X) in tissues.
 However, changes in the Cp are proportional to changes in the amount of drug (X) in
the tissues.
 Since Cp (plasma) is directly proportional to X (tissues),
Cp (plasma) = X (tissues)/Vd;
 Vd being the proportionality constant.
 Therefore, Vd relates the total amount of drug in the body at any time to the
corresponding plasma concentration.

ADME…
 The volume of distribution is an important parameter for determining proper drug

dosing.
 Generally, dosing is proportional to the volume of distribution.
 Vd is useful concentration in relating amount in body to plasma
 Knowing plasma volume (Vp), and Vd the fraction of drug in the body in and
outside plasma can be estimated.
 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑝𝑙𝑎𝑠𝑚𝑎 = Vp/Vd
 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑜𝑢𝑡𝑠𝑖𝑑𝑒 𝑝𝑙𝑎𝑠𝑚𝑎 = Vd − Vp/Vd

ADME…
Factors affecting drug distribution
 Rate of distribution: membrane/tissue permeability, and Blood perfusion;
 Extent of distribution: Physicochemical properties of the drug, and protein binding
capacity.
Drug distribution and tissue permeability
 The rate of blood flow to tissue capillaries varies widely as a result of unequal
distribution of cardiac output to various organs.
 The drug distribution to a particular organ or tissue depends on the size of the tissue
and tissue perfusion rate

ADME…
 Protein binding and ionization will affect transfer rate across membranes, with
only one species (unbound, un-ionized form) capable of traversing membranes
Fig. Blood perfussing a tissue in which distribution

is perfusion rate limited and no elimination occurs.

ADME…
 Drug is presented to a tissue at an arterial blood concentration of CA

Rate of presentation = Q x CA
 The drug leaves the tissue at a venous concentration Cv and at a rate equal to
Q.Cv;
Rate of leaving = Q x Cv
Net Rate of uptake = Q (Cv- CA).

 Drug distribution and Protein binding
 Drugs are transported in the circulating blood in two forms: free form and bound
form.
 Free form of drugs is usually dissolved in plasma and is pharmacologically active,
diffusible, and available for metabolism and excretion.
 Drugs may bind to plasma or tissue proteins
 Plasma-protein binding (PPB):
 Albumin-binding;
 Affects distribution
 PPB drug is pharmacologically inactive
 Non-diffusible
 Not available for metabolism or excretion

ADME…
 The plasma protein binding of drugs is usually reversible

 The binding of individual drugs ranges from very little (e.g., Theophylline) to very
high (e.g. warfarin).
 In circulating blood, there is a constant ratio between the bound and free fractions
of the drug.
 When the concentration of the free drug falls, the free-to-bound ratio is maintained by
dissociation of the bound form of the drug.
 The fraction of drug in plasma unbound (𝑓𝑢) is very important in therapeutics.
𝑓𝑢 = 𝐶𝑢/𝐶
 Where, 𝐶𝑢-is concentration of the unbound drug, and 𝐶-is the concentration in
plasma.
ADME…
 The degree of binding can also be expressed as the bound-to-total concentration

ratio.
 This ratio has values between 0 and 1
 Drugs having values greater than 0.9 are said to be highly bound.
 Because drug may bind to both plasma and tissue proteins, the bound and
unbound drug concentrations must be considered.
 At steady state, unbound drug in plasma and tissue are in equilibration.
Alternatively,

 Where, all terms refer to steady-state condition: fu is the unbound (free) drug fraction in
the plasma, fut is the unbound drug fraction in the tissue, Cu is the unbound drug
concentration in the plasma, and Cut is the unbound drug concentration in the tissues.

Practice Problem
1. Drug A and drug B have Vapp of 20 and 100 L, respectively. Both drugs have a Vp
of 4 L and a Vt of 10 L, and they are 60% bound to plasma protein. Calculate the
fraction of tissue binding of the both drugs?
2. Estimate the volume of distribution for a drug when the volume of plasma and
tissue are 5 and 20L, respectively, and fraction of drug unbound in plasma and
tissue are both 0.7?

ADME…
 Binding is a function of affinity of the proteins to the drug.
 This is characterized by association constant, Ka
 Binding also depends on the molar concentrations of both drug and protein.
 For a single binding site on the protein, the association is simply summarized by the
following reaction:
𝐷𝑟𝑢𝑔+𝑃𝑟𝑜𝑡𝑒𝑖𝑛↔𝐷𝑟𝑢𝑔-𝑃𝑟𝑜𝑡𝑒𝑖𝑛𝑐𝑜𝑚𝑝𝑙𝑒𝑥
 A large variety of drugs ranging from weak acids, neutral compounds, and weak
bases bind to plasma proteins.
 Acidic drugs generally bind albumin and basic glycoproteins;
 Binding to other plasma proteins (e.g., lipoproteins and globulins) occurs to a much
smaller extent
ADME…
 For the majority of drugs, binding to plasma albumin, which comprises >50% of
the total proteins, is quantitatively more important.
 The albumin can bind several compounds having varied structures, some
substances even to a single site.
 Groups of drugs that bind to the same site compete with each other for binding.
Drug binding to tissue Proteins:
 Many drugs accumulate in tissues at higher concentrations than those in the
extracellular fluids and blood called localization.
 Tissue binding of drugs generally is reversible; or some case irreversible (covalent
chemical bonding).

ADME…
 Drug Displacement Interactions

 Drug displacement interactions occur between two or more drugs that bind to same
plasma protein site.
 If one drug is binding to such a site, then administration of second drug having higher
affinity for the same site results in displacement of first drug from its binding site.
 Generally, in many cases, the impact of interactions is minimal
 In some instances a slight displacement of a drug will result in marked increase in its
biological activity.
 E.g. Administration of phenylbutazone to a patient on warfarin therapy results in
displacement of warfarin from its binding site.

Protein Binding Determination
 Spectral Changes in the
 Most drugs have distinct UV spectra because of the conjugated chromophores
molecule.
 Gel Filtration
 This involves the use of porous gels that are molecular sieves.
 Equilibrium Dialysis
 The protein solution (e.g. plasma) containing drug and a buffer solution are placed on
opposite sides of a dialysis membrane.
 Ultrafiltration
 A quicker method of separating free and bound drug is the ultrafiltration method.
 Drug and protein solution are placed in a filter membrane and liquid containing free
drug is forced through membrane by centrifugation.
Elimination Pharmacokinetics
 Elimination is the major process for removal of a drug from the body and
termination of its action.
 It is defined as irreversible loss of drug from body.
 Elimination occurs by two processes, by biotransformation and excretion.
 It is interesting to note that for effective absorption, a drug needs to be sufficiently
lipid soluble
 But it is this same physicochemical property that enables it to bypass excretion.

Elimination….
 Only water-soluble agents undergo renal excretion, whereas lipid soluble

substances are passively reabsorbed from the renal tubules into the blood after
glomerular filtration.
 Thus, if such a phenomenon continues, drugs would accumulate in the body and
precipitate toxic reactions.
 However, to prevent such a consequence, the body is armed with the metabolic
system which transforms the water insoluble, lipophilic, nonpolar drugs into polar
and water-soluble products;
 Can be easily excreted by the kidneys and are poorly reabsorbed .

Disposition of drug in the body as a consequence of metabolism

Biotransformation (Metabolism)
 Results in pharmacological inactivation of drugs, i.e. it results in formation of

metabolites with little or no pharmacological activity
 Occasionally it yields metabolites with equal activity
 Rarely leads to toxicological activation of drugs, i.e. it results in formation of
metabolites with high tissue reactivity
 e.g. conversion of Paracetamol to reactive metabolites that cause hepatic necrosis.
 Inactive drugs (pro-drugs) also depend upon biotransformation for activation, the
process being called as pharmacological activation
 e.g. conversion of enalapril to enalaprilat

Biotransformation…
Drug Metabolising Organs

 Liver is the primary site for metabolism of almost all drugs because of its richness
in large variety of enzymes in large amounts.
 The decreasing order of drug metabolising ability of various organs is:
 Liver > Lungs > Kidneys > Intestine > Placenta > Adrenals > Skin
 Drug metabolising enzymes are versatile and non- specific in metabolising a large
number of drugs.
 The enzymes are broadly divided into 2 categories:
 Microsomal enzymes (M) & Non-microsomal enzymes (N).

 When the drug concentration is low relative to the enzyme concentration, there are
abundant enzymes to catalyze the reaction, and
 The rate of metabolism is a first-order process.
 Saturation of the enzyme occurs when the drug concentration is high, all the
enzyme molecules become complexed with drug, and
 The reaction rate is at a maximum rate; the rate process then becomes a zero-order
process
 The relationship of these parameters is described by the Michaelis–Menten
equation.

 Phase I Reactions
 These reactions generally include oxidative, reductive and hydrolytic reactions.
 This processes, a polar functional group is either introduced or unmasked if
already present on the otherwise lipid soluble substrate,
 e.g. -OH, -COOH, -NH2 and –SH.
 Thus, phase I reactions are also called as functionalization reactions or synthetic
reactions, opposite to the synthetic phase II reactions.
 The resulting product of phase I reaction is susceptible to phase II reactions.

 For example, oxygen is introduced into the phenyl group on phenylbutazone by
aromatic hydroxylation to form oxyphenbutazone, a more polar metabolite.
 Codeine is demethylated to form morphine.
 The hydrolysis of esters, such as aspirin or benzocaine, will yield more polar
products, such as salicylic acid and p-aminobenzoic acid, respectively.
 For some compounds, such as acetaminophen, N-acetyl-P-benzoquinone
imine(NAPQI), and other drugs containing aromatic rings, reactive intermediates,
such as epoxides, are formed during the hydroxylation reaction.
 These aromatic epoxides are highly reactive and will react with macromolecules,
possibly causing liver necrosis

 Phase II Reactions
 These reactions generally involve covalent attachment of small polar endogenous
molecules such as glucuronic acid, sulphate, glycine, etc.
 To either unchanged drugs or phase I products having suitable functional groups viz. -
OH, -COOH, -NH2 and -SH and form highly water-soluble conjugates which are
readily extractable by the kidneys.
 Thus, these reactions are called as conjugation reactions or better known as true
detoxification reactions.
 Since these reactions generally involve transfer of moieties to the substrate to be
conjugated, the enzymes responsible are called as transferases.
 Common examples include the conjugation of salicyclic acid with glycine to form
salicyluric acid or glucuronic acid to form salicylglucuronide
Factors Affecting Biotransformation of Drugs
A) Physicochemical properties of the drug

 Molecular size and shape, pKa, acidity/basicity, lipophilicity and steric and electronic
characteristics of a drug influence its interaction with the active sites of enzymes;
 Stereochemical nature of drug also influences its metabolism;
 Biotransformation requires interaction of a drug with an enzyme, which is an
interaction where spatial arrangement is critical.
B) Chemical Factors
 The phenomenon of increased drug metabolising ability of the enzymes by several
drugs and chemicals is called as enzyme induction and the agents which bring about
such an effect are known as enzyme inducers.

Factor affecting….
 Mechanisms involved in enzyme are:

1. Increase in both liver size and liver blood flow.
2. Increase in both total and microsomal protein content.
3. Increased stability of enzymes.
4. Increased synthesis of cytochrome P-450.
5. Decreased degradation of cytochrome P-450.
6. Proliferation of smooth endoplasmic reticulum

 Inhibition of Drug Metabolizing Enzymes

 A decrease in the drug metabolising ability of an enzyme
 The process of inhibition may be direct or indirect.
 Direct Inhibition:
 I. Competitive Inhibition: results when structurally similar compounds compete
for the same site on an enzyme.
 e.g. Methacholine inhibits metabolism of acetylcholine by competing with it for
cholinesterase.

 II. Non-competitive Inhibition:

 Results when a structurally unrelated agent interacts with the enzyme and prevents
the metabolism of drugs.
 Isoniazid inhibits the metabolism of phenytoin by inhibiting the enzymes non-
competitively. .
 III. Product Inhibition: results when the metabolic product competes with the
substrate for the same enzyme.
 The phenomenon is also called as autoinhibition.

 Indirect Inhibition:
1. Repression: is defined as the decrease in enzyme content.
 It may be due to a fall in the rate of enzyme synthesis as affected by ethionine,
puromycin and actinomycin D or
 Because of rise in the rate of enzyme degradation such as by carbon tetrachloride,
carbon disulphide, disulphiram, etc.
2. Altered Physiology: due to nutritional deficiency or hormonal imbalance.

C) Biological Factors
 Species Differences: due to genetic variation factors;
 Age Variations: make variation in drug metabolism;
 Diet: The enzyme content and activity is altered by a number of dietary
components; For examples:
 Low protein diet decreases and high protein diet increases the drug metabolizing ability.
 Alcohol ingestion results in a short-term decrease followed by an increase in the
enzyme activity.
 Altered Physiological Factors: Pregnancy related conditions and Hormonal
Imbalances;
 Disease States: such as CLD, CHF, CKD, etc

Drug excretion
 Excretion is defined as the process whereby drugs and/or their metabolites are
irreversibly transferred from internal to external environment.
 Almost all drugs and their metabolites are excreted by the kidneys
 Agents that are excreted in urine are:
 Water-soluble.
 Non-volatile.
 Small in molecular size (less than 500 Daltons).
 The ones that are metabolised slowly.

Drug excretion…
 The basic functional unit of kidney involved in excretion is the nephron.

 Each kidney comprises of one million nephrons
 The principal processes that determine the urinary excretion of a drug are:
 Glomerular filtration.
 Active tubular secretion.
 Active or passive tubular reabsorption.

Drug excretion…
 Glomerular filtration and active tubular secretion tend to increase the
concentration of drugs in lumen and hence facilitate excretion whereas tubular
reabsorption decreases it and prevents the movement of drug out of the body.
 Thus, Rate of Excretion = Rate of Filtration + Rate of Secretion – Rate of
Reabsorption
 Glomerular filtration is a non-selective, unidirectional process whereby most
compounds, ionised or unionised, are filtered except those that are bound to
plasma proteins or blood cells;
 The driving force is the hydrostatic pressure, 120 to 130 ml/min is filtered through
the glomeruli, the rate being called as the glomerular filtration rate (GFR).
 Creatinine, inulin, mannitol and sodium thiosulphate are used to estimate GFR
Drug excretion…
 Active tubular secretion

 It is a carrier-mediated process which requires energy against the for
transportation of compounds against concentration gradient.
 The system is capacity-limited and saturable.
 System for secretion of organic acids/anions like penicillins, salicylates,
glucuronides, sulphates, and uric acid are secreted.
 System for secretion of organic bases/cations like morphine, mecamylamine,
hexamethonium and endogenous amines such as catecholamines, choline,
histamine, etc.
 Drugs undergoing active secretion have excretion rate values greater than the
normal GFR value.
Drug excretion…
 Tubular reabsorption
 Reabsorption of a drug is indicated when the excretion rate values are less than the
GFR of 130 ml/min.
 Tubular reabsorption can either be an:
 1. Active process, or 2. Passive process.
 Active tubular reabsorption is commonly seen with high threshold endogenous
substances or nutrients that the body needs to conserve such as
 Electrolytes, Glucose, Vitamins, Amino acids and Uric acid

Drug excretion…
 Passive tubular reabsorption is common for a large number of exogenous

substances including drugs.
 The driving force for such a process i.e. the concentration gradient is established
by the back diffusion or reabsorption of water along with sodium and other
inorganic ions.
 Lipophilic substances are extensively reabsorbed while polar molecules are not.

Drug excretion…
 Since a majority of drugs are weak electrolytes, diffusion of such agents through
the lipoidal tubular membrane depend upon
 PH of the urine.
 Drug pKa:
 Lipid solubility of drugs
 Urine Flow Rate:

 Influence of urinary pH on excretion of weakly acidic and weakly basic drugs.
Bold arrows indicate that the process is predominant.

 Biliary Secretion
 The hepatic cells lining the bile canaliculi produce bile.
 The production and secretion of bile are active processes.
 The bile secreted from liver, after storage in the gall bladder, is secreted in the duodenum.
Bile is important in the digestion and absorption of fats.
 Compounds that are excreted in bile have been classified into 3 categories on the basis of
their bile/plasma concentration ratios:
 Group A compounds whose ratio is approximately 1,
 E.g. sodium, potassium and chloride ions and glucose.
 Group B compounds whose ratio is >1, usually from 10 to 1000,
 E.g. bile salts, bilirubin glucuronide, creatinine, sulphobromophthalein conjugates, etc.
 Group C compounds with ratio < 1,
 E.g. sucrose, inulin, phosphates, phospholipids
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Drug excretion…
 Factors Influence Secretion of Drugs

 In Bile
 1. Physicochemical properties of the drug
 The most important factor governing the excretion of drugs in bile is their molecular
weight.
 Polarity: Greater the polarity, better the excretion.
 Thus, metabolites are more excreted in bile than the parent drugs because of their
increased polarity. e.g. cardiac glycosides.

Drug excretion…
 2. Nature of biotransformation process

 A metabolic reaction that greatly increases the polarity as well as the molecular
weight of drug favours biliary excretion of the metabolite.
 Thus, phase II reactions, mainly glucuronidation and conjugation with glutathione,
result in metabolites with increased tendency for biliary excretion.
 Examples of drugs excreted in the bile as glucuronides are morphine,
chloramphenicol and indomethacin.

Drug excretion…
 Drugs excreted in saliva can undergo cycling in a fashion similar to enterohepatic

cycling,
 e.g. sulphonamides, antibiotics, clonidine, etc.
 Mammary Excretion
 Excretion of a drug in milk is important since it can gain entry into the breast-feeding
infant.
 Milk consists of lactic secretions originating from the extracellular fluid and is rich in
fats and proteins.
 About 0.5 to 1 litre/day of milk is secreted in lactating mothers

Drug excretion…
 Excretion of drugs in milk is a passive process and is dependent upon pH-partition
behavior, molecular weight, lipid solubility and degree of ionization.
 The pH of milk varies from 6.4 to 7.6 with a mean pH of 7.0.
 Free, unionized, lipid soluble drugs diffuse into the mammary alveolar cells passively.
 For acidic drugs, excretion in milk is inversely related to the molecular weight
and partition coefficient and that for basic drugs, is inversely related to the degree
of ionization and partition coefficient

 Some examples of toxicity to breast-fed infants owing to excretion of drug in milk
are:
1. Chloramphenicol: Possible bone marrow suppression.
2. Diazepam: Accumulation and sedation.
3. Heroin: Prolonged neonatal dependence.
4. Methadone: Possible withdrawal syndrome if breast-feeding is stopped suddenly.
5. Propylthiouracil: Suppression of thyroid function.
6. Tetracycline: Permanent staining of infant teeth.
 Wherever possible, nursing mothers should avoid drugs.
 If medication is unavoidable, the infant should be bottle-fed.

Drug clearance
 Clearance is the most important parameter in clinical drug applications and is
useful in evaluating the mechanism by which a drug is eliminated by the whole
organism or by a particular organ
 Clearance is defined as the theoretical volume of body fluid containing drug (i.e.
that fraction of apparent volume of distribution) from which the drug is
completely removed in a given period of time.
 It is expressed in ml/min or litres/hour.

 Total Body Clearance:
 Elimination of a drug from the body involves processes occurring in kidney, liver,
lungs and other eliminating organs.
 Clearance at an individual organ level is called as organ clearance.
 It can be estimated by dividing the rate of elimination by each organ with the
concentration of drug presented to it.
 where D E is the amount of drug eliminated and dD E/dt is the rate of elimination.
 Rearrangement of this Equation yield

 Renal Clearance (CLR):
 It can be defined as the volume of blood or plasma which is completely cleared of the
unchanged drug by the kidney per unit time.
 It is expressed mathematically as: CLR = Rate of Elimination by kidney/C
 Physiologically, renal clearance is the ratio of “sum of rate of glomerular filtration
and active secretion minus rate of reabsorption” to “plasma drug concentration “C”.
 ClR  Rate of filtration  Rate of secretion - Rate of reabsorption

 A first-order elimination rate, dDE/dt, is equal to kDB or kCpVD.
 Substituting elimination rate for kCpVp,

 As the plasma drug concentration decreases during elimination, the rate of drug
elimination, dDE/dt, decreases accordingly, but clearance remains constant.
 Clearance is constant as long as the rate of drug elimination is a first-order process.
 Elimination rate constant (k) represents the sum total of all the rate constants for
drug elimination, including excretion and biotransformation, Cl T is the sum total
of all the clearance processes in the body, including clearance through the kidney
(renal clearance), lung, and liver (hepatic clearance).
Example
1. Penicillin has a ClT of 15 mL/min. Calculate the elimination rate for penicillin
when the plasma drug concentration, Cp, is 2 g/mL.
2. Determine the total body clearance for a drug in a 70-kg male patient. The drug
follows the kinetics of a one-compartment model and has an elimination half-
life of 3 hours with an apparent volume of distribution of 100 mL/kg.

Factors Affecting Renal Clearance
A) Physicochemical properties of the drug
 Important physicochemical factors affecting renal excretion of a drug are - molecular
size, pKa and lipid solubility.
B) Plasma concentration of the drug
 Glomerular filtration and reabsorption are directly affected by plasma drug
concentration since both are passive processes.
C) Distribution and binding characteristics of the drug
 Clearance is inversely related to apparent volume of distribution of drugs.
 Drugs that are bound to plasma proteins behave as macromolecules and thus cannot
be filtered through the glomerulus.
 Drugs extensively bound to proteins have long half-lives because the renal clearance
is small.

D) Blood flow to the kidneys
 The renal blood flow is important in case of drugs excreted by glomerular filtration
only and those that are actively secreted.
 Renal clearance in such instances is said to be perfusion rate- limited.
E) Biological factors
 Age, sex, species and strain differences, differences in the genetic make-up, circadian
rhythm, etc. alter drug excretion.
 Renal excretion is ~10% lower in females than in males.
 The renal function of newborns is 30 to 40% less in comparison to adults and attains
maturity between 2.5 to 5 months of age.
 In old age, the GFR is reduced and tubular function is altered, the excretion of drugs is
slowed down and half-life is prolonged.

 F) Drug Interactions
 Any drug interaction that results in alteration of protein-drug binding
characteristics, renal flood flow, active secretion, urine pH and intrinsic clearance
and forced dieresis would alter renal clearance of a drug.
 The renal clearance of a drug extensively bound to plasma proteins is increased
after displacement with another drug.
 E.g. Gentamicin induced nephrotoxicity by furosemide. Alteration of Urine pH:
 Acidification of urine with ammonium chloride, methionine or ascorbic acid
enhances excretion of basic drugs.
 Alkalinisation of urine with citrates, tartarates, bicarbonates and carbonic
anhydrase inhibitors promote excretion of acidic drugs.

 G) Disease States:
 Renal Impairment
 Renal dysfunction:
 Greatly impairs the elimination of drugs especially those that are primarily excreted by the kidneys.
 Some of the causes of renal failure are HTN, DM, hypovolemia, pyelonephritis,
nephroallergens and nephrotoxic agents such as aminoglycosides, phenacetin and
heavy metals.
 Uraemia:
 Characterized by impaired glomerular filtration and accumulation of fluids and
protein metabolites, also impairs renal clearance of drugs.
 In both these conditions, the half-lives of drugs are increased lead to drug
accumulation and toxicity may result unless dose adjusted

Thank You
Q???
Quiz-2
1. Briefly describe the concept of first-pass metabolism and its significance in the
ADME of orally administered drugs 2pt.
2. Describe the concept of volume of distribution and the factors that influence
drug distribution 2pt.
3. Discuss the importance of plasma protein binding and its impact on the ADME
of drugs 1pt.

ADME Process

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ADME Process

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Drug ADME process

By: Tsegaye N. (B. Pharma., MSc)

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 Many pharmacokinetic studies are concerned principally with the bioavailability

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 The average drug concentration in plasma at steady state during repetitive

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 The rate of disappearance of drug from the gastrointestinal tract is described by

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 where D 0 is the dose of the drug.

 Where, F is the fraction of drug absorbed systemically.

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Zero-order Absorption Process

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 Integration of this equation with substitution of VDCp for DB produces

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 The volume of distribution is an important parameter for determining proper drug

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Fig. Blood perfussing a tissue in which distribution

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 Drug is presented to a tissue at an arterial blood concentration of CA

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 The plasma protein binding of drugs is usually reversible

 The degree of binding can also be expressed as the bound-to-total concentration

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 Drug Displacement Interactions

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 Only water-soluble agents undergo renal excretion, whereas lipid soluble

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 Results in pharmacological inactivation of drugs, i.e. it results in formation of

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Drug Metabolising Organs

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A) Physicochemical properties of the drug

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 Mechanisms involved in enzyme are:

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 Inhibition of Drug Metabolizing Enzymes

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 II. Non-competitive Inhibition:

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 The basic functional unit of kidney involved in excretion is the nephron.

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 Active tubular secretion

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 Passive tubular reabsorption is common for a large number of exogenous