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Pharmacokinetics of oral
absorption
Md. Rakibul Hasan
Department of Pharmacy
International Islamic University
Chittagong
• Systemic drug absorption from GI tract/other
extravascular site depend on:
- Physicochemical properties of drug
-dosage ...
• Oral dosing, factors effect the rate and extent
of drug absorption:
- Surface area of GI tract
- Stomach emptying rate
-...
• Rate of change in the amount of drug in the
body, dDB/dt = dependent on relative rates of
drug absorption and eliminatio...
Plasma level-time curve of drug absorption and
elimination rate processes
Absorption phase- rate of drug
absorption greate...
Zero-order absorption model
• Zero-order absorption- when drug is absorbed
by saturable process/ zero order controlled
rel...
• Rate of 1st order elimination, at any time:
• Rate of input = ko. ∴, net change per unit time
in the body:
• Integration...
First-order absorption model
• Absorption- assume to be 1st order.
• Applies mostly to oral absorption of drugs in
solutio...
• Rate of disappearance of drug from GI:
- ka- 1st order absorption rate constant from GI
- F- fraction absorbed
- DGI- am...
• Rate of drug change in the body:
• =
• Drug in GI- 1st order decline (i.e. drug is
absorbed across GI wall), amount of d...
• Integrate the equation- oral absorption
equation- to calculate drug conc (Cp) in plasma
at any time, t:
(2)
plasma level-time curve for drug given in
single dose
•Max plasma conc after oral dosing –
Cmax
•Time needed to reach max ...
• In order to calculate Cmax- the value of tmax is
determine by equation (4) and substitute to
equation (2).
• Equation (2...
• At later time intervals, when drug absorption
completed, e-kat ≈ 0, equation 2 reduce to
• ln this equation:
• Substitut...
• With equation (5), graph constructed by
plotting log Cp vs. t will yield straight line with
a slope of –k/2.3
• With similar approach, urinary drug excretion
data may be used for calculation of first-order
elimination rate constant,...
• Graph constructed by plotting dDu/dt vs. t,
yield curve identical to plasma level-time
curve
• After drug absorption virtually complete, -e-kat
approaches zero, equation (6) reduces to
• Taking ln of both sides, sub...
• Plot of Du vs t- give urinary drug excretion
curve.
Cumulative urinary drug excretion vs t, single oral
dose. Urine samp...
Determination of Absorption rate
constants from oral Absorption data
Method of residuals
• Assume ka>> k in equation (2), ...
• From this, can obtain the intercept at y-axis
• Value of ka can be obtained by using the
method of residuals as described in chapter
before.
• If drug absorption begins...
Lag time
• sometimes, absorption of drug after single
dose does not start immediately, due to:
- Physiologic factors (stom...
•Lag time- if 2 residual lines obtained by
feathering intersect at point greater than
t=0.
•Lag time t0- beginning of drug...
Determination of ka by plotting % of
drug unabsorbed vs. time (Wagner-
Nelson)
• After single oral dose:
• Ab = DB + Du = ...
• At t = ∞, Cp
∞= 0 (i.e. plasma conc is
neglectable), total amount of drug absorbed:
• Fraction of drug absorbed at any t...
• Fraction unabsorbed at any time is
• Drug remaining in GI at any time, t:
• Therefore, fraction of drug remaining
• DGI/D0 = fraction of drug unabsorbed = 1-(Ab/Ab∞)
• Plot of 1-(Ab/Ab∞) vs. t gives slope = -ka/2.3
• The following steps...
Fraction of drug uabsorbed vs time using Wagner-
Nelson method
•If fraction of drug unabsorbed,
gives linear line, then ra...
Estimation of ka from urinary data
• Absorption rate constant, ka- can be estimated from
urinary excretion data- %of drug ...
• Differential equation for Ab= DB + DE:
• Assuming 1st order elimination with renal
elimination constant ke:
• Assuming o...
• Substitute VDCP into equation (7):
• Rearrange:
• Substitute dCp/dt into equation (8) and kDu/ke
for DE:
(8)
(9)
• Integrate equation (9) from 0 to t:
• At t=∞ all drug is absorbed, expressed as Ab∞
and dDu/dt=0. total amount of drug a...
• Fraction of drug absorbed at any time t=
Abt/Ab∞.
• Plot of fraction of drug unabsorbed, 1-Ab/Ab∞
vs t gives slope = -ka...
Determination of ka from two-
compartment oral absorption data
(Loo-Riegelman method)
• After oral administration of a dos...
• Substitute the above expression for Dp and
Du:
• Divide the above equation with Vp to express
the equation on drug conc:...
• Equation (10) divided by equation (11)-
fraction of drug absorbed at any time:
• Plot of fraction of drug unabsorbed, 1-...
• Cp and k[AUC]t0 calculated from Cp vs time.
• Values for (Dt/Vp) can be approximated by
Loo-Riegelman method:
• Ct = Dt/...
Cumulative relative fraction absorbed
• Fraction of drug absorbed at any time- can be
summed or cumulated
• From equation ...
• In the Wegner-Nelson equation, Ab/Ab∞ or
CRFA- eventually equal unity- 100% (even
though drug may not be 100% bioavailab...
Significance of absorption rate
constant
• Overall rate of systemic absorption surrounded
by many rate processes:
- Dissol...
• Calculation of ka- important in designing
multiple-dosage regimen
• Ka and k allows for prediction of peak and
plasma dr...
Pharmacokinetics of Oral Drug Absorption
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Pharmacokinetics of Oral Drug Absorption

Pharmacokinetics of Oral Drug Absorption

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Pharmacokinetics of Oral Drug Absorption

  1. 1. Pharmacokinetics of oral absorption Md. Rakibul Hasan Department of Pharmacy International Islamic University Chittagong
  2. 2. • Systemic drug absorption from GI tract/other extravascular site depend on: - Physicochemical properties of drug -dosage form used - Anatomy and physiology of absorption site
  3. 3. • Oral dosing, factors effect the rate and extent of drug absorption: - Surface area of GI tract - Stomach emptying rate - GI mobility - Blood flow to absorption site
  4. 4. • Rate of change in the amount of drug in the body, dDB/dt = dependent on relative rates of drug absorption and elimination • The net rate of drug accumulation in the body:
  5. 5. Plasma level-time curve of drug absorption and elimination rate processes Absorption phase- rate of drug absorption greater than rate of drug elimination Elimination occurs whenever drug present- even though absorption predominates At peak drug conc in plasma: Immediately after time of peak drug absorption, some drug may still be at absorption site ( e.g. GI tract. Rate of drug elimination is faster than rate of absorption- postabsorption phase. Drug at absorption site- depleted, rate of absorption approaches 0, dDGI/dt=0 (now elimination phase)- represents only the elimination of drug from the body- 1st order process. Elimination phase- rate of change in the amount of drug in the body- described as 1st order process
  6. 6. Zero-order absorption model • Zero-order absorption- when drug is absorbed by saturable process/ zero order controlled release system • DGI- absorbed systemically at a constant rate, k0. drug- immediately/simultaneously eliminated from body by 1st order process- defined by 1st order rate constant, k.
  7. 7. • Rate of 1st order elimination, at any time: • Rate of input = ko. ∴, net change per unit time in the body: • Integration of this equation, substitute DB= VDCP: • Rate of drug absorption, remain constant until DGI depleted. Time for complete drug absorption = DGI/ko. After this time, drug is not available for absorption from gut, equation 1- not valid. Drug conc in plasma- decline according to 1st order process. (1)
  8. 8. First-order absorption model • Absorption- assume to be 1st order. • Applies mostly to oral absorption of drugs in solution/ rapidly dissolving dosage (tablets, capsules) • Oral drug- disintegrate of dosage form (if solid)- drug dissolves into fluid of GI tract. • Only drug in solution- absorbed in body
  9. 9. • Rate of disappearance of drug from GI: - ka- 1st order absorption rate constant from GI - F- fraction absorbed - DGI- amount of drug in GI at any time, t. • Integration of above equation,
  10. 10. • Rate of drug change in the body: • = • Drug in GI- 1st order decline (i.e. drug is absorbed across GI wall), amount of drug in GI at any time, t = D0e-kat. • Value of F- vary from 0 (drug completely unabsorbed) to 1 (fully absorbed).
  11. 11. • Integrate the equation- oral absorption equation- to calculate drug conc (Cp) in plasma at any time, t: (2)
  12. 12. plasma level-time curve for drug given in single dose •Max plasma conc after oral dosing – Cmax •Time needed to reach max conc- tmax •tmax- independent of dose, dependent on rate constant for absorption, ka and elimination, k •At Cmax- peak conc •Rate of drug absorbed= rate of drug eliminated •Net rate of conc change = 0 •At Cmax- rate of conc change: Can be simplified: (3) (4)
  13. 13. • In order to calculate Cmax- the value of tmax is determine by equation (4) and substitute to equation (2). • Equation (2)- Cmax is proportional to dose of drug given (Do) and F. • Elimination rate constant, k- may determined from elimination phase of plasma level-time curve.
  14. 14. • At later time intervals, when drug absorption completed, e-kat ≈ 0, equation 2 reduce to • ln this equation: • Substitute to log: (5)
  15. 15. • With equation (5), graph constructed by plotting log Cp vs. t will yield straight line with a slope of –k/2.3
  16. 16. • With similar approach, urinary drug excretion data may be used for calculation of first-order elimination rate constant, k • Rate of drug excretion after single oral dose drug: • dDu/dt= rate of urinary drug excretion - Ke = 1st order renal excretion constant - F = fraction of dose absorbed (6)
  17. 17. • Graph constructed by plotting dDu/dt vs. t, yield curve identical to plasma level-time curve
  18. 18. • After drug absorption virtually complete, -e-kat approaches zero, equation (6) reduces to • Taking ln of both sides, substitute for log • When log (dDu/dt) vs. t, graph of straight line is obtained with slope of –k/2.3. • To obtain the cumulative drug excretion in urine:
  19. 19. • Plot of Du vs t- give urinary drug excretion curve. Cumulative urinary drug excretion vs t, single oral dose. Urine samples are collected at various time period. The amount of drug excreted in each sample is added to amount of drug recovered in previous urine sample. Total amount of drug recovered after all drug excreted is Du∞ Du∞- max amount of active drug excreted
  20. 20. Determination of Absorption rate constants from oral Absorption data Method of residuals • Assume ka>> k in equation (2), the value of 2nd exponential will become significantly small (e- kat ≈0)- can be omitted. When this happen= drug absorption is virtually complete.
  21. 21. • From this, can obtain the intercept at y-axis
  22. 22. • Value of ka can be obtained by using the method of residuals as described in chapter before. • If drug absorption begins Immediately after oral admin the residual lines obtained will intercept on the y axis at point A
  23. 23. Lag time • sometimes, absorption of drug after single dose does not start immediately, due to: - Physiologic factors (stomach-emptying time and intestinal motility) - Time delay prior to commencement of 1st order drug absorption- lag time
  24. 24. •Lag time- if 2 residual lines obtained by feathering intersect at point greater than t=0. •Lag time t0- beginning of drug absorption. •Equation to describe lag time: Second expression that describes the curve omits lag time:
  25. 25. Determination of ka by plotting % of drug unabsorbed vs. time (Wagner- Nelson) • After single oral dose: • Ab = DB + Du = amount of drug absorbed • Ab∞= amount of drug absorbed at t= ∞ • Amount of drug excreted at any time t: • DB, at any time = CpVD. At any time t, Ab is
  26. 26. • At t = ∞, Cp ∞= 0 (i.e. plasma conc is neglectable), total amount of drug absorbed: • Fraction of drug absorbed at any time
  27. 27. • Fraction unabsorbed at any time is • Drug remaining in GI at any time, t: • Therefore, fraction of drug remaining
  28. 28. • DGI/D0 = fraction of drug unabsorbed = 1-(Ab/Ab∞) • Plot of 1-(Ab/Ab∞) vs. t gives slope = -ka/2.3 • The following steps use in determination of ka: 1. Plot log conc of drug vs. t 2. Find k from terminal part of slope, -k/2.3 3. Find [AUC]t0 4. Find k[AUC]t0 by multiplying each [AUC]t0 by k 5. Find [AUC]∞0 by adding up all the [AUC], from t=0 to t=∞ 6. Determine 1-(Ab/Ab∞) value corresponding to each time point t 7. Plot 1-(Ab/Ab∞) vs. t
  29. 29. Fraction of drug uabsorbed vs time using Wagner- Nelson method •If fraction of drug unabsorbed, gives linear line, then rate of drug absorption, dDGI/dt- 1st order process •Drug approaches 100% absorption, Cp- becomes small- the terminal part become scattered- not included for estimation of slope. 1-(Ab/Ab∞)
  30. 30. Estimation of ka from urinary data • Absorption rate constant, ka- can be estimated from urinary excretion data- %of drug unabsorbed vs time. • For one-compartment model: - Ab= total amount of drug absorbed - DB= amount of drug in body - Du= amount of unchanged drug excreted from urine - Cp= plasma drug conc - DE= total amount of drug eliminated - Ab= DB + DE
  31. 31. • Differential equation for Ab= DB + DE: • Assuming 1st order elimination with renal elimination constant ke: • Assuming one-compartment model: (7)
  32. 32. • Substitute VDCP into equation (7): • Rearrange: • Substitute dCp/dt into equation (8) and kDu/ke for DE: (8) (9)
  33. 33. • Integrate equation (9) from 0 to t: • At t=∞ all drug is absorbed, expressed as Ab∞ and dDu/dt=0. total amount of drug absorbed is: • Du∞= total amount of unchanged drug excreted in urine
  34. 34. • Fraction of drug absorbed at any time t= Abt/Ab∞. • Plot of fraction of drug unabsorbed, 1-Ab/Ab∞ vs t gives slope = -ka/2.3, in which absorption rate constant, ka obtained.
  35. 35. Determination of ka from two- compartment oral absorption data (Loo-Riegelman method) • After oral administration of a dose of drug exhibit two-compartment model, amount of drug absorbed, Ab: • Each can be expressed as:
  36. 36. • Substitute the above expression for Dp and Du: • Divide the above equation with Vp to express the equation on drug conc: • At t=∞, this equation become (10) (11)
  37. 37. • Equation (10) divided by equation (11)- fraction of drug absorbed at any time: • Plot of fraction of drug unabsorbed, 1-Ab/Ab∞ vs time gives –ka/2.3 as a slope from which the value of ka is obtained.
  38. 38. • Cp and k[AUC]t0 calculated from Cp vs time. • Values for (Dt/Vp) can be approximated by Loo-Riegelman method: • Ct = Dt/Vp, apparent tissue conc. • (Cp)tn-1 = conc of drug at central compartment for sample n-1.
  39. 39. Cumulative relative fraction absorbed • Fraction of drug absorbed at any time- can be summed or cumulated • From equation , the term Ab/Ab∞ becomes cumulative relative fraction absorbed (CRFA).
  40. 40. • In the Wegner-Nelson equation, Ab/Ab∞ or CRFA- eventually equal unity- 100% (even though drug may not be 100% bioavailable.
  41. 41. Significance of absorption rate constant • Overall rate of systemic absorption surrounded by many rate processes: - Dissolution of drug - GI motility (ability to move spontaneously) - Blood flow - Transport of drug across capillary membrane to systemic circulation • Rate of drug absorption- net result of this processes
  42. 42. • Calculation of ka- important in designing multiple-dosage regimen • Ka and k allows for prediction of peak and plasma drug conc. following multiple dosing

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