Pharmacokinetics and Biopharmaceutics: Absorption and Bioavailability Notes

Learning Objectives

• Interpret concentration-time data from extravascular administration:

  • Lag time for absorption: Understand the initial delay before the drug appears in the plasma. This delay includes the time for drug dissolution, movement to the absorption site, and penetration across biological membranes. Factors such as the drug's formulation (e.g., immediate-release vs. extended-release) and physiological conditions (e.g., gastric emptying rate) can influence lag time.

  • Flip-flop kinetics: Differentiate between absorption-rate-limited and elimination-rate-limited kinetics to optimize drug delivery. Recognize that in flip-flop kinetics, the absorption rate is slower than the elimination rate, leading to a prolonged terminal phase. Consider how drug characteristics (e.g., solubility, molecular size) and route of administration (e.g., oral, intramuscular) affect the rate-limiting step.

• Estimate bioavailability from pharmacokinetic data: Accurately determine the fraction of the administered dose that reaches systemic circulation. Account for factors such as first-pass metabolism, incomplete absorption, and distribution into tissues. Understand the importance of bioavailability in determining appropriate dosing regimens and achieving therapeutic drug concentrations.

• Understand bioavailability and factors influencing it: Identify physiological and pharmaceutical factors affecting drug absorption and metabolism. Physiological factors include gastric pH, intestinal motility, and blood flow to the absorption site. Pharmaceutical factors include drug formulation, particle size, and excipients.

Absorption: 1 Compartment Distribution

• Can be described as a sum of exponentials: Plasma concentration curves following extravascular administration are multi-exponential. The multi-exponential nature reflects the various processes involved in drug absorption, distribution, and elimination.

• Lines don't intersect at t=0, indicating a delay ("lag") in absorption: This lag represents the time it takes for the drug to dissolve and be absorbed into the systemic circulation. The absence of intersection at t=0 suggests that absorption does not begin immediately upon administration. Factors such as gastric emptying, drug dissolution rate, and membrane permeability can influence the lag time.

• The exponent lines cross when absorption begins, which is t=0 if absorption starts immediately after taking the dose (normal case). Otherwise, a delay in the commencement of absorption has occurred in this case as the lines cross at t>0. This delay can be due to factors such as the drug's formulation (e.g., enteric coating), the presence of food in the gastrointestinal tract, or physiological conditions affecting drug dissolution and absorption.

Absorption: Flip-Flop Kinetics

• Terminal or elimination phase differs following i.m. and i.v. administration: The route of administration affects the rate-limiting step in drug disposition. Intramuscular (i.m.) administration may result in slower absorption compared to intravenous (i.v.) administration, leading to differences in the terminal elimination phase.

• Terminal phase represents the slowest process; absorption is the slowest process: In flip-flop kinetics, absorption rather than elimination governs the terminal slope. This occurs when the absorption rate constant (ka) is significantly smaller than the elimination rate constant (k).

• Curve stripping involves back-extrapolating the terminal phase to isolate the "absorption" phase: This technique helps estimate the absorption rate constant. By graphically separating the absorption and elimination phases, key parameters such as ka and k can be determined.

• If CL (clearance) and Vd (volume of distribution) haven't changed, a line parallel to the i.v. data represents k (elimination rate constant): Allows comparison between i.v. and extravascular routes. Superimposing i.v. and extravascular data helps assess the relative contributions of absorption and elimination to the overall drug disposition.

• In this case, the terminal slope following i.m. injection is determined by absorption (ka).

• Without IV data, it's impossible to confirm flip-flop kinetics: An i.v. reference is essential to differentiate between absorption- and elimination-limited kinetics. Comparing the terminal slopes of i.v. and extravascular data allows for definitive determination of flip-flop kinetics.

• Flip-flop PK (pharmacokinetics) is an exception, likely with slowly absorbed pharmaceuticals, such as:

  • i.m. injections

  • Implants

  • Slow-release tablets

  • Poorly soluble drugs

• The only way to be sure is to compare against the terminal slope of an i.v. dose.

• If the equation for the line is set up incorrectly, it will result in a negative AUC (Area Under the Curve).

• Flip-flop kinetics can be used to one's advantage to create sustained-release formulations, resulting in a smoother concentration-time profile. It reduces peak concentrations and extends the duration of therapeutic effect. By controlling the absorption rate, drug levels can be maintained within the therapeutic window for a prolonged period.

Bioavailability

• Bioavailability (F): Fraction of an extravascular dose that reaches the systemic circulation intact. Affected by:

  • Dissolution/Absorption (FABS): The rate and extent to which a drug is released from its dosage form and absorbed across biological membranes. Factors such as particle size, crystal form, and the presence of excipients can influence drug dissolution and absorption.

  • First-pass metabolism after oral administration:

    • Gut wall metabolism (FG): Enzymes in the gut wall can metabolize the drug before it reaches the liver. Enzymes such as cytochrome P450s and UDP-glucuronosyltransferases (UGTs) in the intestinal epithelium can contribute to first-pass metabolism.

    • Hepatic metabolism (FH): The liver's enzymatic activity reduces the amount of drug reaching systemic circulation. The liver is the primary site of drug metabolism, with enzymes such as cytochrome P450s, UGTs, and sulfotransferases playing key roles.

• For oral administration: $F = F<em>{ABS} \times F</em>G \times F_H$

• Factors impacting bioavailability are:

  • Efflux: P-glycoprotein: Transporters like P-gp can pump drugs out of cells, reducing absorption. P-gp actively transports drugs out of intestinal cells back into the gut lumen, reducing their absorption into the systemic circulation.

  • Drug in solution in the GIT (Gastrointestinal Tract): A drug must be in solution to be absorbed. Only drugs in solution can be passively or actively transported across the gastrointestinal membrane.

Bioavailability: Calculation

• After IV administration:

  • No dissolution/absorption (FABS).

  • No gut wall metabolism (FG).

  • No first-pass metabolism (FH).

  • 100% of the dose enters the circulation directly.

  • Only elimination from the circulation occurs (CL).

  • AUC is determined by Dose and CL: $AUC_{0-\infty} = \frac{Dose}{CL}$

• After an extravascular dose, the entire dose may not reach the circulation.

  • The amount reaching the circulation is determined by F and the dose: Dose reaching the circulation = F x Dose administered

    • $CL = \frac{F \times Dose}{AUC_{0-\infty}}$

    • $AUC_{0-\infty} = \frac{F \times Dose}{CL}$

Bioavailability: Calculation Formula

• If we know the Dose and AUC for an i.v. dose and an extravascular (“ex”) dose, we can calculate F:

  • $\frac{AUC<em>{ex}}{AUC</em>{iv}} = F \frac{Dose<em>{ex}}{Dose</em>{iv}}$

  • $F = \frac{AUC<em>{ex}}{Dose</em>{ex}} \div \frac{AUC<em>{iv}}{Dose</em>{iv}}$

• Assuming CL is constant:

  • $\frac{AUC<em>{ex}}{AUC</em>{iv}} = F \times \frac{Dose<em>{ex}}{CL} \div \frac{Dose</em>{iv}}{CL}$

Bioavailability: Calculation Example

• Given:

  • $Dose_{iv} = 50mg$

  • $AUC_{iv} = 200 \frac{mg \cdot h}{L}$

  • $Dose_{ex} = 100mg$

  • $AUC_{ex} = 100 \frac{mg \cdot h}{L}$

• Calculation:

  • $F = \frac{100}{100} \div \frac{200}{50}$

  • $F = 1 \div 4$

  • $F = 0.25$

• Expected result.

Bioavailability: Identifying the Components

• After IV administration:

  • No dissolution / Absorption (FABS)

  • No gut wall metabolism (FG)

  • No first-pass metabolism (FH)

  • Only elimination from the circulation as the drug flows around the body (CL).

• We know that: $CL<em>T = CL</em>H + CL<em>R + CL</em>{other} …..$

Bioavailability: Calculation of Components

• $F = F<em>{ABS} \times F</em>G \times F_H$

• If we know/calculate $CL_T$ and:

  • Assume there is no $CL_R$

  • Or we know what $CL_R$ is

• Then we know $CL<em>H (=CL</em>T – CL_R)$

• We know that: $CL<em>H = Q</em>H \times E_H$

  • $Q_H$: Hepatic blood flow

  • $E_H$: Extraction ratio

• If we assume that $Q<em>H$ is 1.5 L/min, then we can calculate $E</em>H$: $E<em>H = \frac{CL</em>H}{Q_H}$

• We know that the fraction escaping metabolism (i.e. FH) is 1 – the fraction extracted: $F<em>H = 1 – E</em>H$

Bioavailability: Calculating FG

• $F = F<em>{ABS} \times F</em>G \times F_H$

• The total amount of:

  • Unchanged parent drug in urine + metabolites from all sources (urine, feces etc…)

  • Must equal the amount absorbed (FABS)

• Now we can calculate $F<em>G$: $FG = \frac{F}{F{ABS} \times F</em>H}$

Why Bother With These Things?

• $F<em>G = \frac{F}{F</em>{ABS} \times F_H}$

• Example:

  • A dose of 100 mg was administered orally

  • A total 80% of the dose was recovered as unchanged parent drug in urine + metabolites in urine and feces

  • $F_{ABS} = 0.8$

  • Total CL is 0.9 L/min

  • $E<em>H = \frac{CL}{Q</em>H} = 0.6$

  • $F<em>H = 1-E</em>H = 0.4$

  • F = 0.24 (comparison of iv and oral data)

  • $F_G = \frac{0.24}{(0.8 \times 0.4)}$

  • $F_G = 0.75$

Bioavailability: Oral Administration - Detailed Breakdown of a 100 mg Oral Dose

• 80 mg was absorbed: $0.8 \times 100$

• 20 mg was not absorbed: $100 – 0.8 \times 100$

• 60 mg was not metabolised in gut wall: $80 \times 0.75$

• 20 mg was metabolised in the gut wall: $80 - 80 \times 0.75$

• 36 mg was metabolised by the liver: $60 – 60 \times 0.4$

• 24 mg reached the systemic circulation intact: $60 \times 0.4$

  • $F = F<em>{ABS} \times F</em>G \times F_H = (100 \times 0.8 \times 0.75 \times 0.4) = 24 mg$

Simplification

• $F = F<em>{ABS} \times F</em>G \times F_H$

• $F_g$ is very rarely if ever calculated.

• For the purposes of this course, we will simplify things and combine $F<em>{ABS}$ and $F</em>G$ to result in: $F = F<em>{ABS} \times F</em>H$

Importance of Bioavailability

• Bioavailability can range 0-1 (0-100%)

  • Felodipine F = 4 to 36%

  • Amlodipine F > 80%

• The same drug may have a different bioavailability for different routes of administration.

• Different drugs may have a different bioavailability for the same route of administration.

• Disease or environmental factors may affect the bioavailability of drugs in different ways.

Importance of Bioavailability: Dosage Adjustment

• We can use bioavailability to correct for any differences to administer an appropriate dose to obtain the desired exposure for safe and effective therapy.

• Changes in F have more serious clinical consequences in drugs with low bioavailability

  • Small changes can result in large changes in amount reaching the circulation

  • If F increases from 5% to 10% this is a 100% increase in dose reaching the circulation!

Importance of Bioavailability: Factors Affecting Bioavailability

• Alteration of enzyme and transport protein activity in the liver and gut wall

  • Food, e.g. grapefruit juice

  • Drugs/herbal supplements (e.g. St Johns Wort)

  • Environmental factors -smoking (other hydrocarbons)

  • Liver