kinetics exam 2 - oral absorption Flashcards

1
Q

Two formulations of the same drug, A and B, have different absorption rates. A has a faster absorption rate than B. B will arrive at peak concentration in a shorter time.

A
True

B
False

A

false because since A has a faster absorption time it will reach the peak concentration sooner

they are the same drug so they have the same elimination rate tho

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2
Q

ABSORPTION SITES SUCH AS
G-I TRACT

what different variables mean

A

A—Measured form of Drug
B—Moiety Chemically Appended to A
A + B—Molecular form of Drug

S = A/(A+B)
Dgi = A + B

F = fraction of drug absorbed

for IV, the F is always 1 because all of the drug goes to the blood and is absorbed

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3
Q

Model for Absorption from Extravascular Sites: Two Compartments

A

Absorption: mostly first-order, but can be zero-order.

central compartment (Cp, VD, DP) k goes out
Tissue compartment (Ct, Vt, Dt)

k12 and k21 goes between the central and tissues compartments

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4
Q

Model for Absorption from Extravascular Sites: One Compartment

A
  1. Anatomy and physiology of absorption site
  2. Physico-chemical properties of drug
  3. Dosage form used

absorption goes in
DB, VD
elimination goes out

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5
Q

Model for Absorption from Extravascular Sites II

A

Anatomy and Physiology: factors such as GI motility, and surface area for absorption

  • Dosage Form Used: for instance if solid, needs to first disintegrate, then dissolve in GI fluids before absorption is possible
  • Physico-chemical properties of drug: e.g. lipid solubility, size etc…
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6
Q

Oral Absorption: Cp against t Curve

A

absorption Phase: Rate of absorption > rate of elimination
- the graph line goes up

Cmax: peak concentration
- rate of absorption = rate of elimination

Post-Absorption Phase:
Rate of absorption < rate of elimination
- line begins to go down

Elimination Phase: Rate of absorption = 0
- line steadily goes down

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7
Q

Importance of Parameters

A

ka (the first-order rate constant for absorption) and k make it possible to determine peak and trough plasma concentrations during multiple dosing

  • Changes in ka and k affect the Cmax, tmax, and AUC. If ka increases at a steady k, Cmax increases and tmax decreases while AUC remains the same. However at a steady ka, if k increases, Cmax, tmax, and AUC all decrease.
  • ka, k, and tmax are useful in determining the bioequivalence of chemically equivalent products

makes sense because ka is absorption so if it increases and k (which is elimination) decreases then Cmax will increase and tmax will decrease because it will take less time to reach the tmax

makes sense because k is elimination so if it increases then Cmax & tmax will decrease

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8
Q

do problem!

A

slide 11

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9
Q

Zero-Order Absorption Process

A

The selection of a model and order is typically based on the data gathered

  • Zero order absorption occurs when the process is saturable or when a controlled-release system is used.
  • For a zero-order absorption with rate constant k0 and a first-order elimination with rate constant k:
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10
Q

First-Order Absorption Process II

A

CpSFkaD0 (e-kt-e-kat) VD(ka –k)

At time tmax, corresponding to peak plasma concentration, Cmax, dDB/dt = 0 and so
differentiating,:

so at time tmax, peak plasma concentration is 0

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11
Q

do the problem!

A

slide 15, 16, 17

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12
Q

First-Order Absorption Process: Determining the Elimination rate Constant (k)

A
  • During the elimination phase e-kat  0. Thus:
  • Taking natural logarithms and then substituting with common logarithms:

eqn resembles y = mx + b

Thus k is determined from the slope of the log Cp against t curve; other parameters may be determined from the intercept (FkaD0/VD(ka – k))

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13
Q

graph

A

the y-intercept that is extrapolated from the straight line is this eqn
(FD0ka)/(VD(ka-k)

the slope of the elimination line = -k/2.3

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14
Q

First-Order Absorption Process: Determining the Elimination rate Constant (k) II

A

Similarly, urinary excretion data may be used. The urinary rate of excretion:

Thus k may be determined from the slope of the log dDu/dt against t curve; other parameters may be determined from the intercept (Fka keD0/ (ka – k))

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15
Q

graph!

A

slide 21

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16
Q

First-Order Absorption Process: Determining the Elimination rate Constant (k) III

A

Thus k may be determined from the slope of the log dDu/dt against t curve; other parameters may be determined from the intercept (Fka keD0/ (ka – k))

17
Q

do the problem!

18
Q

First-Order Absorption Process: Determining the Elimination rate Constant (k) IV

A
  • Since dDU/ dt cannot be determined for any single time point, the value for each time point on the previous plot is first obtained by taking urine samples over a period for assay (DU/ t is plotted against time t). The average rate over each period is determined and the time used is the mid point of each such period.
    /k
  • The cumulative parent drug excreted in the
    urine at time t =  : D  = Fk D Ue0
19
Q

Determining k and ka

A
  • -Method of Residuals:
    The amount of absorbable drug at the absorption site at time t

D D e-kat
-where D0 is the amount of absorbable drug at time zero

Fraction of unabsorbed drug:
DGI e-kat D0
or
log -
D0 2.3

20
Q

Determining Absorption Rate Constant ka : Method of Residuals

A
  • From equation

a plot of Cp against time may be used to determine ka: the elimination phase slope is –k/2.3 and the y-intercept (FkaD0/VD(ka – k)) = A

21
Q

Determining Absorption Rate Constant ka : Method of Residuals II

A

ka can be obtained by using the feathering technique:
by extrapolating the elimination phase line on the semilog plot, A can be obtained

a line representing the absorption phase is obtained by subtracting points on the extrapolated beta line from the corresponding original observed data points

a plot of the values of the differences gives a straight line with slope –ka/2.3

22
Q

graph

A

slide 28, 29

23
Q

Example for Method of Residuals

do the problem

24
Q

when do you use -Wagner-Nelson and -Loo-Riegelman

A

Wagner-Nelson - used only for 1 compartment

-Loo-Riegelman - used for 2 or multiple compartments

25
Determining Absorption Rate Constant ka : Wagner-Nelson Method
* This method assumes a one-compartment model D0 = DGI + DB + DU where DU is the amount of unchanged drug in the urine * Amount of drug absorbed: Ab=DB +DU At time t = , Ab = 0 + kVD[AUC]0t
26
Determining Absorption Rate Constant ka : Urinary Data
Recall: only valid urine samples will yield accurate pharmacokinetic parameters
27
Determining Absorption Rate Constant ka : Urinary Data II
Making the relevant substitutions and integrating from time zero to t and zero to  respectively:
28
Flip-Flop of ka and k
Generally, using the feathering technique, ka > k i.e. ka represents the steeper slope * A reversal of the values of these rate constants can occur when they are estimated from oral absorption data * This occurs for drugs with very fast elimination (k > ka). Reversal occurs for some drugs with k > 0.69/hr such as isoproterenol and salicyluric acid. It could also occur for an extended-release product if ka drops well below k. * Thus in order to be sure that ka > k (as would be indicated by oral data), the drug must be given to the same patient intravenously. * A drug with a high value for k (short t1/2) is probably not suitable for oral administration. drug with high Ka may not be suitable for ROA that requires absorption
29
graph of the flip flop of ka and k
REMEMBER, while doing the method of residuals the ka will always be greater than the k ka > k k > ka when the flip flop method occurs for drugs with high elimination rates such as isoperonterol and salicyulic acid (I think that is how you spell them lol)
30
Absorption and Lag Time
Factors such as stomach emptying time and intestinal motility create a lag time in some individuals i.e. a delay in absorption * Absorption begins at the end of lag time (t0); onset time, on the other hand, represents the time needed for drug levels to attain the minimum effective concentration * In taking lag t0 into account, earlier equation must be re- expressed as: * On the Cp against time curve, if the intersection of the two residual lines falls to the right of the origin, the x-axis value is t0. why is there a lag time after you take ibuprofen, but the drug does not show up in the blood immediately because you may have had a large meal or the drug does not disintegrate