This document provides an overview of pharmacokinetics concepts related to drug absorption, distribution, metabolism and elimination in the body. It discusses how drugs move through membranes via passive diffusion or active transport processes. Key determinants of absorption include a drug's lipid solubility and ionization state, which affect its ability to pass cell membranes. The liver plays a major role in drug metabolism and elimination through first-pass clearance of orally administered drugs. Pharmacokinetic parameters like volume of distribution, clearance and half-life help characterize a drug's disposition in the body.

1. Module 2- Pharmacokinetics and Drug
Metabolism
Absorption and Distribution
Drug molecules move around the body either by bulk flow (in bloodstream, lymphatic) or
diffusion.
Most drugs fall within the molecular weight range of 200-1000 Da.
Cell membranes form barriers between aqueous compartments of the body- separates
intercellular and extracellular compartments.
Moat drugs are given orally and must pass through the gut wall to enter the blood stream.
An epithelial barrier such as the gut consists of a layer of cells tightly connected to each other
that molecules must transverse at least 2 cell membranes to pass from one side to the next.
There are gaps between endothelial cells that act as filter allowing small molecules through.
4 main ways of crossing membranes
Passive diffusion- follows concentration gradient, across membranes via pores (has to be small
molecules)
Passive lipid diffusion- highly relevant to drug absorption
By combination with solute carrier
Pinocytosis- trapping in vesicle and released once get into target cell- used for macromolecules
like glucose.
The absorption process is affected by many factors but is usually proportional to the lipid
solubility of a drug.
Lipid Diffusion
Non ionized molecules is favored because the latter are far more lipid soluble than ionized
(charged molecules) molecules which are surrounded by a shell of water molecules.
Most drugs are weak acids or bases. Acids include aspirin and diazepam/ Bases include
amphetamine and climetidine.
Ionization determines how well a molecule moves between aqueous and lipid media.
Ionization ↓ lipid solubility ↑ which gives then ↑ membrane diffusion (and vice versa)
Drugs are absorbed mainly from the small intestine because of the large surface area. Drugs
absorbed from gastrointestinal tract enter portal circulation and some are extensively
metabolised as they pass through the liver.
Drugs that are sufficiently lipid soluble to be readily absorbed orally are rapidly distributed
thorough the body water compartment.
The number of molecules crossing the membrane per unit area in unit time is determined by the
permeability coefficient P and the concretion difference across membrane.

2. There is a close correlation between lipid solubility and the permeability of the cell membrane to
different substances. For this reason lipid solubility is one of the most important determinants of
a drug in terms of pharmacokinetics – rate of absorption form gut, penetration into different
tissues and extent of rate of elimination can be predicted knowing drug lipid solubility.
Henderson- Hasselbach Equation
Relates the ratio of protonated to unprotanated acid or base to its pKA and the pH of the medium.
Many drugs are weak acids or base their sate of ionization varies with pH according to the
Henderson- Hasselbach equation. Only the uncharged species (protonated form for weak acid,
unprotanated for weak base) can diffuse across lipid membrane, this gives rise to pH partition. pH
partition means that weak acids tend to accumulate in compartments of relatively high pH whereas
weak bases do reverse. pH affects how much of a drug is absorbed, where drug is distributed and at
which rate drug is excreted. Strong bases of pKa of 10 or higher and acids of pKa 3 or less are not
absorbed.
Routes of Administration
1. Oral
- 75% of drugs are given orally
- Safest method
- Drug is subject to first pass metabolism
- Some drugs destroyed by acid or enzymes in the gut (gastrointestinal motility)
- Oral route absorption affected by: gastric emptying (rate limiting, food slows gastric
emptying and decreases absorption, splanchnic blood flow), pH (ionization effect, low
pH inactivate some antibiotics) and formulation.
- Major site of absorption is the small intestine due to its large surface area. Little drugs
are absorbed in the stomach.
2. Sublingual
- From blood vessels at base of tongue
- Lipid soluble drugs only and small surface area (potent drugs only)
- Avoids first pass effects
3. Intravenous
- Dangerous
- Direct entry into circulation and bypasses the absorption barrier
- Used when rapid effect is required, for continuous administration (infusion), for large
volumes, drugs that cause local tissue damage if given by other routes.
4. Intrathecal
- Injection into CSF usu via spinal column
- Spinal anesthesia and chemotherapy
- Bypasses blood brain barrier

3. 5. Intramuscular
- Drugs with low water solubility unsuitable for oral administration
- Avoids first pass metabolism
- Penicillin
- Painful
6. Other - Eyes and Nose/ Subcutaneous ( slow, even absorption, insoluble suspensions, avoids
first pass metabolism)/ rectal (severe vomiting or unconscious patients)
Drug Disposition
Clearance
- Important concept in pharmacokinetics- efficiency of drug elimination
- Irreversible elimination from circulation/ one way elimination
- It is the volume of blood or plasma cleared of drug in unit time.
- Clearance is the sum of individual clearance values (total clearance + metabolic
clearance + renal clearance + other clearances).
Volume of Distribution
- The volume into which the total amount of a drug in the body would have to be
uniformly is distributed to provide concentration of the drug actually measured in the
plasma- apparent rather than real volume.
- Used to calculate loading dose
- It is back calculated from concentration of drug plasma following given dose
Half Life
- Time taken for concentration of drug in blood to fall by half its original value – single
dose
- Has 2 phases half life of distribution and half life of elimination
- Determined by clearance and volume distribution
- Exponential curve of plasma concentration against time
- Double dose increases duration by one half life
Bioavailability
- term used to describe portion of administered drug reaching the systemic circulation
- 100 % in intravenous but drugs orally have only portion reaching systemic circulation as
drugs are subject to high degree of first pass metabolism.
- Absorption- extent intact drug absorbed from gut into portal circulation (fg)

4. - First pass clearance-extent drug removed by liver from portal circulation on way to
systemic circulation
- Bioavailability- fraction of dose reaching systemic circulation intact (F)
- F= fg x fh
- For example morphine- almost completely absorbed from gut – hepatic (liver) extraction
is around 67% thus bioavailability of morphine is around 33%.
- Plasma protein binding- drugs only reach receptors if it’s free and many drugs bind to
plasma protein mainly albumin.
Metabolism of Drugs