GW BGZ2026 Practical - Computer lab assignment pharmacokinetics

What is pharmacokinetics?

Pharmacokinetics describes what the body does to a drug over time. It includes the processes of absorption, distribution, metabolism, and excretion (ADME). These processes determine the drug concentration in the blood and tissues and therefore influence onset, intensity, and duration of action.

What are the two core pharmacokinetic parameters?

1. Volume of distribution (Vd) – describes how extensively a drug distributes into body tissues compared to plasma.

2. Clearance (CL) – describes the body's ability to eliminate a drug per unit time.

Together, they determine drug concentration, half-life, and dosing requirements.

What is the difference between pharmacokinetics and pharmacodynamics?

• Pharmacokinetics (PK): What the body does to the drug (ADME).

• Pharmacodynamics (PD): What the drug does to the body (receptors, effects, MEC, toxicity thresholds).

What is a decadic (base-10) logarithm?

A decadic logarithm answers: “To what power must 10 be raised to obtain a number?”

log₁₀(x) = y means 10ʸ = x.

Example:

• log₁₀(100) = 2 because 10² = 100.

Why are logarithmic scales important in pharmacology?

Many biological and drug-related variables span several orders of magnitude (e.g., plasma concentrations). A log scale compresses this wide range into manageable numbers. It also makes exponential processes (like drug elimination) appear linear.

What is the pharmacological significance of pH being logarithmic?

pH = −log₁₀[H⁺]

This means:

• A 10× change in hydrogen ion concentration equals 1 pH unit.

• Small pH changes represent large chemical changes affecting drug ionization and absorption.

What is the relationship between log values and fold changes?

• +1 log unit = 10× increase

• +2 log units = 100× increase

• −1 log unit = 10× decrease

This is crucial for interpreting drug concentration changes.

What is drug absorption?

Absorption is the movement of a drug from its site of administration into the systemic circulation. It determines how much and how fast a drug reaches the blood.

What factors affect drug absorption?

• Lipid solubility (higher → better absorption)

• Ionization (non-ionized form absorbs better)

• Surface area (small intestine > stomach)

• Blood flow

• Gastric emptying rate

• Food and drug interactions

• Formulation and stability

What is bioavailability (F)?

Bioavailability is the fraction of an administered dose that reaches systemic circulation unchanged.

F = (amount reaching circulation) / (administered dose)

• IV: F = 1 (100%)

• Oral: F < 1 due to incomplete absorption and first-pass metabolism

What is the difference between rate and extent of absorption?

• Extent: Total amount absorbed → determines bioavailability (AUC).

• Rate: Speed of absorption → determines onset and peak concentration (Cmax, Tmax).

What are key differences between IV and oral administration?

• IV: immediate effect, 100% bioavailability, no absorption phase

• Oral: slower onset, variable absorption, first-pass metabolism reduces F

• IV produces higher and earlier Cmax than oral administration

What is drug distribution?

Distribution is the reversible movement of a drug between blood and tissues. It depends on blood flow, tissue binding, and physicochemical properties of the drug.

What is volume of distribution (Vd)?

Vd = Amount of drug in body / Plasma concentration

It is an apparent volume that describes how extensively a drug distributes.

• High Vd → extensive tissue distribution

• Low Vd → stays in plasma

Why can Vd exceed total body water?

Because Vd is not a real physical volume. It reflects how much drug leaves the bloodstream and binds in tissues. Lipophilic drugs can accumulate in fat and tissues, producing very large Vd values.

What is drug metabolism?

Drug metabolism is the enzymatic conversion of lipophilic drugs into more polar, water-soluble metabolites to facilitate excretion.

Why is metabolism necessary?

Because lipophilic drugs:

• Are reabsorbed in renal tubules

• Are poorly excreted

• Would accumulate without transformation

Metabolism prevents prolonged drug action and toxicity.

What are the main sites of drug metabolism?

• Liver (primary site)

• Intestinal wall

• Kidney

• Lung

• Skin (minor)

What are Phase I reactions?

Phase I reactions introduce or expose functional groups:

• Oxidation

• Reduction

• Hydrolysis

They increase polarity and prepare drugs for Phase II metabolism.

What are Phase II reactions?

Phase II reactions conjugate drugs with endogenous molecules (e.g., glucuronic acid, sulfate), producing highly water-soluble metabolites that are usually inactive.

What is the cytochrome P450 system?

A major enzyme system in the liver responsible for Phase I oxidation reactions. It metabolizes most drugs and is a major source of drug interactions.

Key isoenzymes: CYP3A4, CYP2D6, CYP2C9.

What is drug excretion?

Excretion is the removal of drugs and metabolites from the body via urine, bile, lungs, sweat, saliva, or breast milk.

What are the renal excretion processes?

• Glomerular filtration (free drug only)

• Tubular secretion (active transport)

• Tubular reabsorption (depends on ionization and pH)

What is enterohepatic recycling?

Drug excreted in bile is reabsorbed from intestine back into circulation, prolonging drug half-life.

What is clearance?

Clearance is the volume of plasma from which a drug is completely removed per unit time.

CL = rate of elimination / plasma concentration

It determines:

• Maintenance dose

• Steady-state concentration

• Drug elimination rate

Higher clearance → lower drug levels and shorter half-life.

What is half-life (t½)?

Half-life is the time required for drug concentration to decrease by 50%.

t½ = 0.693 × Vd / CL

It determines:

• Time to steady state (~4–5 half-lives)

• Duration of drug action

• Dosing interval

• Time for drug elimination

What is the relationship between clearance, volume of distribution, and half-life?

t½ = (0.693 × Vd) / CL

• Large Vd → longer half-life

• High clearance → shorter half-life

What is steady-state concentration?

Css = Dose rate / Clearance

At steady state, drug input equals drug elimination.

What determines AUC?

AUC = (F × Dose) / CL

AUC reflects total systemic drug exposure.

What determines dosing rate?

Dose rate = Css × CL

Used to design maintenance dosing regimens.

What determines initial IV concentration?

C₀ = Dose / Vd

High Vd → lower initial plasma concentration.

How do you calculate dose in IV administration and what does it represent?

Dose is the total amount of drug administered to the body. In IV administration, it is calculated as:

Dose = Volume × Concentration

Example:
0.5 mL × 2 mg/mL = 1 mg

This represents the exact amount of drug entering systemic circulation immediately, since IV administration bypasses absorption barriers and first-pass metabolism.

Why does intravenous administration result in an immediate peak concentration (C₀)?

IV administration delivers the drug directly into systemic circulation, meaning:

• No absorption phase is required

• Bioavailability is 100% (F = 1)

• Drug instantly distributes into plasma and tissues

Thus:
C₀ = Dose / Vd

The only factor limiting initial concentration is the apparent volume into which the drug distributes, not absorption speed.

What happens to the pharmacokinetic curve when dose increases?

Increasing dose causes a proportional vertical shift in the concentration-time curve:

• C₀ increases

• Cmax increases

• AUC increases proportionally

However:

• Clearance (CL) remains unchanged

• Half-life (t½) remains unchanged

• Elimination rate constant (ke) remains unchanged

This is because dose changes input, not elimination capacity.

Thus, the entire curve becomes “higher,” but retains identical shape and slope.

Why does increasing dose increase AUC but not clearance or half-life?

AUC represents total systemic exposure:

AUC = (F × Dose) / CL

When dose increases:

• More drug enters the system

• Clearance does not change because it is a physiological constant

Therefore:

• AUC increases proportionally to dose

• Half-life remains unchanged because it depends on Vd and CL only

Thus, AUC reflects exposure, not elimination speed.

What happens when volume of distribution increases?

Increasing Vd means drug distributes more extensively into tissues.

Effects:

• C₀ decreases (drug leaves plasma more rapidly)

• Plasma concentration becomes lower

• Half-life increases (drug is “hidden” in tissues)

• Elimination constant (ke) decreases

• AUC remains unchanged

Because:

• Total drug in body is unchanged

• Only distribution between compartments changes

Clinically:
Drugs with high Vd often have long duration of action due to tissue storage.

What happens when clearance increases?

Clearance determines how efficiently the body eliminates drug.

When CL increases:

• Drug is removed faster

• AUC decreases

• Half-life decreases

• ke increases

• Steady-state concentration decreases

C₀ remains unchanged because it depends only on dose and Vd.

Clinically:
Increased clearance often leads to therapeutic failure unless dose is adjusted.

Why is half-life determined by both volume of distribution and clearance?

Half-life reflects both:

• How widely the drug distributes (Vd)

• How quickly it is eliminated (CL)

Formula:
t½ = (0.693 × Vd) / CL

Interpretation:

• Large Vd → drug remains in body longer → longer t½

• High CL → faster elimination → shorter t½

Thus:
half-life is not a direct property of dose, but of body handling of drug.

Why is clearance considered constant while elimination rate is not?

Clearance is a physiological constant representing organ efficiency (kidney, liver, etc.).

However:
Rate of elimination = CL × C

So:

• When concentration is high → elimination rate is high

• When concentration is low → elimination rate is low

Thus:

• CL is constant

• Elimination rate is concentration-dependent

This produces exponential decay rather than linear elimination.

Why does drug concentration decrease in a curved (not linear) pattern?

Because elimination depends on current concentration:

Rate of elimination = CL × C

As C decreases:

• Elimination slows automatically

• Each time interval removes a smaller absolute amount

This creates:

• Rapid early decline

• Slower later decline

• Exponential decay curve

On a semi-log plot, this becomes linear.

Why do IV and oral administration produce different Cmax and AUC values?

IV administration:

• Immediate entry into blood

• F = 1 (100% bioavailability)

• Highest possible Cmax

• Full AUC exposure

Oral administration:

• Requires absorption (ka-dependent)

• First-pass metabolism reduces F

• Lower Cmax due to slower entry

• Lower AUC if F < 1

Key principle:

• IV = dose-limited exposure

• Oral = absorption + metabolism-limited exposure

What is the effect of changing absorption rate constant (ka)?

ka determines how quickly drug enters systemic circulation.

High ka:

• Rapid absorption

• Sharp rise in concentration

• High Cmax

• Early Tmax

Low ka:

• Slow absorption

• Blunted peak

• Delayed Tmax

• Lower Cmax

• Prolonged exposure

ka does NOT change AUC (if dose and F unchanged), only curve shape.

Why does IV infusion reach a plateau (steady state)?

During infusion:

• Drug enters body at constant rate

• Drug is eliminated continuously

Initially:

• Input > elimination → concentration rises

Over time:

• Higher concentration → higher elimination (CL × C)

Eventually:

• Input = elimination → steady state reached

Thus:
Css = Dose rate / CL

Why does volume of distribution not affect steady-state concentration?

At steady state:

Css = Dose rate / CL

Vd is not part of this equation because:

• It affects distribution equilibrium

• It does not affect elimination capacity

Therefore:

• Vd affects time to reach Css

• But not the value of Css itself

What happens when dose rate increases during infusion?

• Css increases proportionally

• Curve rises to a higher plateau

• Early slope becomes steeper

Because:
more drug enters per unit time while clearance remains constant.

What happens when clearance increases during infusion?

• Css decreases

• Steady state reached at lower concentration

• Elimination is faster

Because:
drug is removed more efficiently per unit time.

What are MEC, MTC, and the therapeutic window?

• MEC (Minimum Effective Concentration): lowest concentration producing therapeutic effect

• MTC (Minimum Toxic Concentration): lowest concentration causing toxicity

• Therapeutic window: range between MEC and MTC

Clinical goal:
Maintain drug concentration within this window for efficacy without toxicity.

Are MEC and MTC pharmacokinetic or pharmacodynamic parameters?

They are pharmacodynamic (PD) parameters because they describe:

• Drug effect on the body

• Therapeutic and toxic thresholds

• Not drug movement or concentration changes

PK determines concentration; PD determines effect thresholds.

What happens when dose is increased in repeated dosing?

• Higher peak concentrations (Cmax ↑)

• Higher trough concentrations

• Greater accumulation

• Increased risk of toxicity (exceeding MTC)

Steady state still occurs, but at a higher average concentration.

What happens when dosing interval is shortened while keeping total daily dose constant?

Example:
100 mg every 12h → 50 mg every 6h

Effects:

• Lower peak concentrations

• Higher trough concentrations

• Reduced fluctuations

• More stable plasma levels

Conclusion:
Smaller, more frequent dosing smooths concentration curves.

What do repeated oral dosing and IV infusion have in common?

Both systems:

• Reach steady state after ~4–5 half-lives

• Show accumulation before steady state

• Achieve equilibrium when input = elimination

• Are governed by clearance

Difference is only in input pattern:

• Continuous (infusion)

• Intermittent (oral dosing)

How do you design a dosing regimen to stay within the therapeutic window?

Goal:
Maintain concentration between MEC and MTC.

Strategy:

• Increase dose if below MEC

• Decrease dose if above MTC

• Shorten dosing interval to reduce fluctuations

• Use loading dose for rapid effect

• Use maintenance dose for steady-state control

Best approach:
Smaller, more frequent doses → smoother curve → safer therapy.

What happens to drug levels when clearance decreases due to kidney failure?

• Clearance decreases

• Half-life increases

• Drug accumulates

• Css increases if dose is unchanged

• Higher risk of toxicity

Clinical response:
Dose reduction or increased dosing interval is required.

How do you calculate rate of elimination?

Rate of elimination (mg of drug/min) = clearance x Cpl

Cpl is plasma concentration

CL is a constant

High Cpl → high rate of elimination and the other way around.

What does half-life determine?

1. Time to reach steady state (during repeated dosing or infusion)

When a drug is given repeatedly or by continuous infusion, it gradually accumulates until input = elimination.

• After 1 half-life → ~50% of steady state reached

• After 2 half-lives → ~75%

• After 3 half-lives → ~87.5%

• After 4 half-lives → ~93.75%

• After 5 half-lives → ~96–97% (practically steady state)

So, half-life determines how long it takes for the drug to “build up” to a stable level in the body.

2. Time to eliminate a drug after stopping it

When dosing stops, the same rule applies in reverse:

• After 1 half-life → 50% remains

• After 2 half-lives → 25% remains

• After 3 half-lives → 12.5% remains

• After 5 half-lives → ~3% remains (clinically negligible)

So, half-life determines how long a drug “stays in the body” after stopping treatment.

3. Dosing interval (clinical scheduling)

Half-life helps decide how often a drug should be given:

• Short half-life → frequent dosing (e.g., multiple times per day)

• Long half-life → once daily or even less frequent dosing

4. Degree of accumulation

If dosing happens before the previous dose is fully eliminated:

• Short half-life drugs → little accumulation

• Long half-life drugs → significant accumulation