ADME

Drug disposition

To achieve its effect, whether therapeutic or toxic, a drug and/or its metabolites must be present in appropriate concentrations at its sites of action.

All drugs are poisons. Some are more poisonous than others.

Xenobiotic = any foreign compound to an organism’s normal metabolism

• Deliberate – drugs, food additives
• Accidental – food contaminants, pesticides
• Coincidental – industrial chemicals, environmental pollutants

There are many different types of drugs (formulation and dosage) and many different ‘types’ of patients (dose-response relationship).

The dose-response relationship is made up of two parts:

• The dose-concentration relationship (ADME) is the most important in drug development in bridging from animal studies to the human situation and the mathematical description of the rates of these processes and of concentration-time relationships = pharmacokinetics

• Age
• Gender
• Organ function
• Drug interactions – i.e. intercurrent medications
• Drug metabolising capacity
• (Physiological status)
  • The concentration-response relationship = pharmacodynamics

The concentration of xenobiotic attained will depend on:

• Dose
• Formulation
• Route of administration (ROA)
• Rate and extent of absorption (A)
• Distribution through the body and binding to tissues (D)
• Biotransformation (M)
• Excretion (E)

 

A

Absorption is the process by which the xenobiotic gains entry into the systemic circulation

• GIT – most important
• SKIN – main barrier between internal milieu and external environment
• RESP – volatile compounds/ aerosols/ dust particles

Regardless of the site of absorption, xenobiotics must cross cell membranes to enter the systemic circulation. This (mechanistically) can occur in one of two ways:

• Small lipophilic compounds can cross cell membrane by passive diffusion along a concentration gradient

• concentration gradient across lipid bilayer
• lipid: water partition coefficient of the drug
  • Large, highly polar or charged compounds cannot cross the cell membranes by simple diffusion, and hence are dependent on the presence of active carrier-mediated transport mechanisms

Many xenobiotics are weak acids/ weak bases (i.e. present in solution in ionised and non-ionised forms) – the partition of weak electrolytes across the cell membranes will thus be a function of the pKa of the xenobiotic and the pH gradient across the membrane:

• Low pH in stomach favours absorption of weak acids
• Rapid absorption of both weak acids (pK > 3) and weak bases (pK < 7.8) in intestines

First-pass metabolism

• Gut wall
• Hepatocytes (others but less so e.g. lung, skin…)

 

D

Distribution refers to the drugs movement from the systemic circulation to the various body tissues.

Most tissue membranes behave as typical lipid barriers – drug distribution is thus affected by:

• Tissue haemodynamics
• Passive diffusion across lipid membranes
• Presence of carrier-mediated active transport processes recognising the xenobiotic

• If a drug enters a tissue by an active transport mechanism, its concentration in the tissue may be many times greater than its plasma concentration
  • Protein binding in the blood and tissues – so that extensively bound drugs have only limited access to tissues
• Acidic drugs tend to bind to albumin
• Basic drugs tend to bind to α₁-acid glycoprotein

Drug reservoirs – the storage of a drug can prolong its action either within the tissue where the drug is held or at a distant site reached following rediffusion into the systemic circulation e.g. thiopental

Three factors affect protein binding:

1. Affinity of certain drugs to bind with plasma proteins
2. Number of binding sites available for drug at any given time
3. Drug distribution

 

M

A drug may be eliminated (or retained) unchanged, undergo spontaneous chemical transformation, or it may be enzymatically metabolised (biotransformed) before its elimination.

Enzymatic metabolism can occur at extrahepatic (often sites of entry and/or exit of the drug) sites such as lungs, kidney, GIT mucosa; or more predominantly by the liver.

1. Compounds eliminated unchanged are generally either

1. Highly polar such as strong carboxylic or sulfonic acids (e.g. sodium cromoglycate) or quaternary amines (e.g. pancuronium) – if absorbed, these drugs are rapidly cleared into urine or bile
2. Volatile – readily lost via lungs
   2. In contrast, non-polar highly lipophilic compounds may be retained for long periods in tissue lipids e.g. polyhalogenated aromatics
   3. For a small number of compounds, spontaneous chemical transformation within the tissues of the body can be important
3. Hydrolysis (at appropriate pH)
4. Reaction with nucleophilic/electrophilic centres in tissue macromolecules e.g. nucleophilic –SH of glutathione
   4. Mostly drugs will undergo a part of an immense scope of possible metabolism, typically in a biphasic manner
5. Functionalization reaction (oxidation, reduction, hydrolysis, hydration, condensation) by CYP450 which introduces/uncovers a functional group (-OH, -NH2, -SH) suitable for
6. Subsequent conjugation (with an endogenous conjugating agent)

Cytochrome P450

• Terminal oxidase component of the microsomal electron transfer system (is responsible for oxidation of many xenobiotics)
• Required electrons supplied by closely associated enzyme NADPH-cytP450-reductase (a flavoprotein)

• Transfers 2 electrons to cytP450 (from NAD(P)H)
  • Enzyme superfamily (of related isoenzymes)
• All possess iron protoporphyrin IX as prosthetic group
• Named for Sonet band 450 nm exhibited by CO complex of the reduced form
• Grouped together into (10 mammalian) families comprised of 18 subfamilies
  • 1A, 2B, 2C, 2D, 3A are the most important ones
  • Individual enzymes use the same catalytic mechanism but show different substrate specificity
  • this selectivity is highly variable within an isoform
  • substrate is often metabolised at more than one position

Conjugation reactions

Phase II (conjugation) reactions are divided into two distinct groups depending on the source of energy for the process:

Activated endogenous conjugating agent (most common)

• Glucuronic acid – e.g. indomethacin, paracetamol, clofibrate, morphine

• Family of glucuronyl transferase enzymes located in ER of cells of liver, intestine and kidney
  • Catalyse conjugation of uridine-diphosphate-α-1-glucuronic acid with nucleophilic O, N, C and S atoms 1-O-substituted B-D-glucopyranosiduronic acids
  • MW 50-60 kDa
  • Exist as oligomers of between 1-4 subunits
  • At least 9 different isozymes in 2 different subfamilies
• Sulfation – e.g. catecholamines, phenols, alcohol

• Widespread in tissues
  • Methylation –
  • Acetylation – e.g. N-Acetyl Transferase (liver, intestine) and polymorphism
• “slow acetylator”: INH peripheral neuropathy
• “fast acetylator”: toxic metabolite of INH

Derived by prior metabolic activation of the xenobiotic

• Glutathione

• Glutathione-S-transferases catalyse conjugation of a number of functional groups (aryl/alkyl halides, lactones, epoxides, quinones) with glutathione (γ-glutamylcysteinylglycine tripeptide)
  • Extensively distributed throughout tissues
  • Principally in cytosol especially liver where also important in intracellular binding – e.g. bilirubin, oestradiol, cortisol, testosterone, tetracyclines, penicillin
  • MW 24-28 kDa existing as dimers
• Amino acid conjugation

Factors Influencing (rate and extent of) Metabolism

• Physicochemical – electrophilicity/ nucleophilicity/ lipophilicity/ polarity/ protein binding
• Endogenous – age/ sex/ species/ strain/ pathology/ genetic deficiency/ cofactor availability
• Exogenous – dose, nutrition, ROA, diurnal, enzyme inhibition/induction

The intracellular concentration of a chemical is primarily dependent on dose size and its physicochemical and structural properties.

Role of Metabolism in Toxicity

Reactive intermediates, either unstable or even stable ones such as the metabolite of chloramphenicol causing blood dyscrasias.

Bioactivation of chemicals can result from almost all the enzymes of drug metabolism, even the conjugations.

Factors determining the toxic responses:

1. Nature of ultimate reactive species
2. Role of target molecules in cell function – especially energy supply and integrity of cell membranes and enzyme systems
3. Effectiveness of cellular defences in detoxifying active species and repairing initial damage

 

E

In both kidneys and liver, polar compounds are excreted more efficiently than lipophilic compounds.

Renal excretion

Filtration

Polar/charged and little binding to plasma proteins e.g. aminoglycosides, vancomycin

Secretion

Drugs removed from plasma and actively secreted into proximal tubules – weak acids and basic substrates each in a relatively non-selective process (i.e. xenobiotics of similar charge compete for transport)

Reabsorption

Lipid soluble compounds are extensively reabsorbed within the tubules (and hence poorly eliminated by the kidneys) along a concentration gradient for weak electrolytes. (Note: urine pH is highly variable excretion rates of weak electrolytes

Biliary excretion

For excretion of larger lipophilic compounds which may be extensively (size (MW), polar group, and chemical structure) protein-bound – at least 3 ATP-dependent transport systems involved:

• Gp170 (P-glycoprotein) – lipophilic/cations e.g. digoxin, opioids

• Multi-drug resistance seen with chemotherapeutics
  • Gp110 – unipolar steroids e.g. bile acids
  • MOAT (Multi-specific Anion Transporter) – bilirubin and its conjugated metabolites, ampicillin, ceftriaxone, oubain

Enterohepatic circulation: excretion of drug conjugate hydrolysis in intestines reabsorption parent compound. Many xenobiotics despite extensive biliary cycling will ultimately be excreted in the urine.

Other routes

• Pulmonary – e.g. anaesthetic gases/vapours
• Saliva
• Breast milk

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“The whole in vitro ADME space from Solution Properties, Drug Absorption & Transport, Drug Metabolism and Drug-Drug Interactions” – Pharmaron