1. Variability of Hepatic Drug Metabolism & Dosage Adjustment

2. Objectives
Discuss hepatic disease and other factors which impact hepatic drug metabolism.
Review calculations of Hepatic extraction and clearance.
Understand the impact of hepatic first pass extraction on oral bioavailability.
Based on the extraction ratio, estimate whether the clearance of a drug will be mainly dependent on liver blood flow rate or intrinsic enzyme activity.
Calculate hepatic clearance, extraction, half-life and dosage requirements based on changes in blood flow and intrinsic metabolic activity in patients.

3. HEPATIC CLEARANCE
Important drug clearance route. Most lipid-soluble drugs are metabolized by one or more enzymes within the liver.
As liver is major metabolic organ, generally consider hepatic clearance as metabolism. However drugs and their metabolites can also be secreted from hepatocytes into bile. Biliary Secretion
Hepatic disorders caused by multitude of diseases.
- Has impact on a number of metabolic enzyme systems and physiological factors within the liver.

4. HEPATIC DISEASE
2 Major types of Liver Disease
Cirrhosis- Hepatoctyes replaced by non-functional connective tissue.
- Permanent loss of functional hepatocytes.
- Portal vein hypertension and shunting of blood flow around liver.
-  Liver blood flow
-  Production of plasma proteins
Hepatitis- Inflammation of liver causing
 function or cell death of hepatocytes.
Acute- Mild/ Transient changes in hepatic function
Chronic - Often irreversible hepatocyte damage
- Can progress to cirrhosis.

5. Effect on Metabolism 1) Enzyme Activity/Capacity
- Effects on drug metabolism may be different depending on enzyme system.
Cirrhosis :
Generally see  Drug metabolism
require dosage adjustment.
Acute Viral Hepatitis:
Some drugs changed
approx 50% of drugs affected

6. Alterations in Hepatic Clearance (CLH) and F (Liver Bioavailability )
2) Hepatic Blood Flow:
 Q in chronic liver disease (cirrhosis, alcholism, hepatitis).
portal blood shunted (bypass liver)
PK EFFECTS:
Alterations in Hepatic Clearance (CLH) and F (Liver Bioavailability )
DOSES OF METABOLIZED DRUGS OFTEN NEED TO BE REDUCED

7. Genetic polymorphisms Exposure to drugs/ environmental Age
Likewise enzyme capacity/ affinity and/or liver blood flow also affected by :
Genetic polymorphisms
Exposure to drugs/ environmental
Age
Physiological Factors
Activity, cardiac output
Other Diseases
Inflammatory disease
Renal disease
All important sources of variability in hepatic clearance.

8. Hepatic Clearance CL H = Q (ER) LIVER Blood IN
Blood OUT
25% Hepatic Artery
75% Portal Vein
Hepatic Vein
Bile
Remember:
Physiological definition of Hepatic Clearance is dependent on Blood flow (Q) to the liver and Efficiency of the liver to clear the drug from blood.
CL H = Q (ER)

9. CLH : Hepatic Clearance
Q: Flow rate through liver
ER: Hepatic Extraction Ratio
(0-1)
represents the proportion of drug entering liver that is metabolized or excreted upon EACH pass through the liver.
ER= CLH/Q

10. Plasma vs Blood Q = Liver Flow Blood: Q = 1.5 L/min
Plasma Q = 825 ml/min
Use:
Plasma flow with plasma clearance &
Blood flow with blood clearance
Q plasma = (1- HCT) Q blood
HCT = hematocrit
The fraction of blood volume
which is taken up by erythorcytes.
Average HCT = 0.45

11. Drug can be removed by liver in two manners:
Removal of drug from the systemic circulation
Hepatic Clearance- (CLH) is a component of total body clearance.
Drug dissolved in blood/plasma is removed during each pass through liver.
2) Pre-systemic removal of drug (1st pass)
Drug is directly absorbed into portal vein and exposed to liver prior to entry into systemic circulation.
Removal of drug upon the 1st pass through liver decreases oral bioavailability.
Hepatic 1st pass Extraction is a component of oral bioavailability.

12. Need to consider systemic availability for orally administered drugs.
Therefore, Liver extraction efficiency impacts both systemic hepatic clearance (hepatic clearance) and oral bioavailability (1st pass effect) of drugs.
Need to consider systemic availability for orally administered drugs.
Fraction remaining after 1st pass thru liver (fer ) :
fer = 1 - ER
fer Liver bioavailability,
liver first pass availability.
But also need to consider absorption!

13. so F would be equal to fer
Bioavailability (F)
Oral bioavailability (F) involves a combination of processes:
- dissolution in gut (fdis)
- absorption (fabs)
- liver first pass (fer)
F = fdis x fabs x fer
If entire dose is absorbed :
fdis = 1 , fabs = 1
so F would be equal to fer
Remember:
F * Dosepo = Doseiv

14. Problem
A new drug Zee® is completely eliminated through hepatic metabolism to inactive metabolites.
After a 100 mg IV dose to healthy patients, plasma samples were collected, a total body clearance (CLT) of mL/min
was calculated.

15. Q1. What is the predicted hepatic ER of Zee® ?
ER = CLH / QH -

16. Q2. Assuming complete intestinal absorption, what is the equivalent oral dose of Zee® ?
fer = 1-ER

17. Q3. If the intestinal absorption of Zee® is incomplete (70%) - what oral dose is required?
F = fdis x fabs x fer

18. Hepatic extraction is dependent on several factors that can change
Not always so simple…..
Hepatic extraction is dependent on
several factors that can change

19. Calculation of ER based on mechanism
ER dependent on:
1. Uptake of drug (partitioning)
2. Amt of enzyme
3. Metabolic activity (Vmax, km)
4. Blood flow (Qh)
1, 2 & 3 = Intrinsic clearance (CLint)
ER = CL int__
CLint + Qh
Capacity
& Affinity

20. CLint + Qh ( Qh -CLH) CL int = CLH * Qh
Other important equations describing
this relationship:
Substituting ER with CLH
(ER= CLH/Q) to describe in terms of CLH:
CLH = Qh * CL int_
CLint + Qh
Rearrangement of equation to describe relationship in terms of CL int :
CL int = CLH * Qh
( Qh -CLH)

21. CLint – Intrinsic clearance
CLint – Intrinsic clearance. The inherent ability of the liver to metabolize drugs in the absence of limitations. Ideal situation. Reflects total enzyme activity.
CLH- “actual clearance” – based on intrinsic enzyme activity and limitations (factors which limit access to metabolic enzymes).
These equations allow us to describe CLH and ER based on liver blood flow and enzyme parameters

22. Intrinsic enzyme activity can change:
Describing clearance in all possible terms (ie- using the more complex equations, which factor in CLint) allows us to estimate drug clearance when physiologic or disease conditions causes changes in either liver blood flow or intrinsic enzyme activity.
Intrinsic enzyme activity can change:
Genetic polymorphisms
Environmental pollutants
enzyme induction
Drug-drug interactions
enzyme induction/ inhibition.
- Hepatic Disease
Liver Blood flow can change:
Activity ( Q)
Posture
Food ( Q)
Hepatic Disease
Changes in cardiac output

23. Estimating Impact of Changes
Relative impact of changes in Q or enzyme activity (Clint) on the hepatic clearance, bioavailability or half-life of a drug depends on how efficiently the drug is removed/extracted by the liver
Generally ***…..
High: ER > 0.7
Very efficiently removed from liver.
Low: ER< 0.3
Low efficiency in extraction
Intermediate ER
****This an arbitrary division of groups – there is no absolute ranking system.

24. Typical drug examples
High ER :
Verapamil, lidocaine, propranolol, nitroglycerin, cocaine, morphine
Intermediate ER:
Aspirin, Quinidine
Nortriptyline
Low ER:
Antipyrine, NSAIDs, Diazepam,
Erythromycin, Phenytoin
Theophylline, Warfarin
* Low ER does not mean it is not metabolized.

25. Hepatic Clearance (CLH)
Impact of variability in Q and enzyme function on
Hepatic Clearance (CLH)

26. Clint >>> Qh CLH  Qh * CL int_ CLint  CLH  Qh
Highly Extracted Drugs
Clint >>> Qh
CLH  Qh * CL int_ CLint
CLint terms cancel out.
 CLH  Qh
Hepatic clearance approximates blood flow.
Qh is limiting factor
Flow dependent/limited.
CLint is approx
equal to
( CLint + Qh )

27. Qh >> CL int CLH  CL int (ER<0.3) Low Extracted Drugs
So (Clint + Q) is approx equal to Q
CLH  Qh * CL int_ Qh
CLH  CL int
Hepatic Clearance approximates inherent metabolic activity.
CLint is limiting factor
CAPACITY LIMITED.
CLH = Qh * CL int_
CLint + Qh

28. Effect of Physiological changes on CLH
Based on this…should be able to make”quick” initial prediction on drug metabolism & clearance for high and low extracted drugs.
No shortcuts for Intermediate Extraction drugs.
Relative changes in ER (bioavailability) will be differentially affected by changes in Q or CLint .
The relative tendency after moderate changes.
For instance if blood flow decreases to 0 ……
You should be calling 911, not estimating hepatic clearance.
Dramatic changes will affect clearance of all drugs.

29. Dosage Route 1) IV doses 2) Oral doses
-Consider effects on hepatic clearance and t½.
2) Oral doses
- Consider effects on 1st pass through liver (fer) , hepatic clearance and t½
- 1st pass is an important parameter for High E drugs.
- Since so much drug enters liver on 1st pass, both Qh and CL int are important
- If Q too fast: ed access to enzymes

30. Impact of Variability of liver blood flow and enzyme activity on oral bioavailability.

31. * fer is dependent on BOTH
fer = 1 - ER
= 1- [ CL int/ (CLint+Qh)]
fer = __Qh___
CL int + Qh
High ER: CL int >> Qh
fer  Qh / CL int
substitute in equation
for ER as defined by CLint
* fer is dependent on BOTH
Qh and CLint

32. Change in Blood Flow: Sample Problem
Two drugs (A & B) are completely metabolized in the liver by CYP2D6.
The following is known about A & B*
* Blood data. Qh = 1.5 L/min
DRUG V (L) CLT (L/min) t1/2 (hr) A B
Intestinal absorption is complete for both drugs.
Q. Determine expected CLT, t1/2 and F of Drug A & B in congestive heart failure patients which have a 40%  in cardiac output
- 40%  CO

33. Solution:
(CO by 40%) then Q  by 40%
Assume CL int is unchanged
Calculate original CL int
- based on original values of Q & CLH.

34. ii) Determine CLH
use new Q and original CL int

35. iii) Determine t½ using new CLT
(CLT = CLH)
- assume V not changed

36. iv) Calculate ER
- use new CLH and new Q
v) Calculate fer using new ER

37. Summary of Problem Set Original 40%  Qh Drug A Clint L/min Low E
0.167
CLH L/min
0.15
0.14 F
0.9
0.84
t½ hr
2.3
2.5
Drug B
CLint L/min
High E
13.5
CLH L/min
1.35
t½ hr
0.1
0.26
0.06
0.41

38. ER = 0.1 ER = 0.9  LIVER BLOOD FLOW CLH ↑ t½ IV  fer CLH PO
High ER: fer  Qh / CL int

39. Changes in Enzyme Activity. Problem –part B
Two drugs (A & B) are completely metabolized in the liver by CYP2D6.
The following is known about A & B*
* Blood data. Qh = 1.5 L/min
DRUG V (L) CLT (L/min) t1/2 (hr) A B
Intestinal absorption is complete for both drugs.
Q. Calculate the expected CLT, t1/2 and F of Drug A & B in patients with CYP2D6 polymorphism that is associated with 50 %  in enzyme activity ( 50 %  CLint ).

40. Assume only CLint changes, - no change in Q.
Solution :
Assume only CLint changes,
- no change in Q.
Calclulate original CL int .
ii) Calculate new CL int .
Polymorphism: 50%  CL int

41. CLint + Qh iii) Determine CLH - use new CL int and original Q
CLH = Qh * CL int_
CLint + Qh

42. iv) Determine t1/2 using new CLT (CLT = CLH)
- assume V not changed

43. v) Calculate ER using new CLH
- with original Q
vi) Calculate fer

44. Summary of Problem Set Original 50%  Clint Drug A Clint L/min Low E
0.167
0.084
CLH L/min
0.15
0.079 F
0.9
0.95
t½ hr
2.3
4.4
Drug B
CLint L/min
High E
13.5
6.75
CLH L/min
1.35
1.23
t½ hr
0.1
0.26
0.18
0.28

45. ER = 0.1 ER = 0.9  INTRINSIC CLEARANCE CLH ↑t½ IV CLH ↑t½ PO
 F PO
High ER: fer  Qh / CL int

46. Applied Biopharm & PK 5th Ed.
Review graphs depicting general changes in plasma drug concentration time curves with alterations in Q or CLint
- -
Page 342 –343
Applied Biopharm & PK 5th Ed.

47. Dosage Adjustment in patients
Still talking about the same two drugs…
The standard daily oral dose required to obtain a therapeutic steady state concentration in normal patients is: Drug A = 25 mg
Drug B = 200 mg
Q. Calculate the oral dose of Drug A and Drug B required in patients with the CYP2D6 polymorphic SNP varients (50% activity).

48. Css = FN *DOSEN = FP *DOSEP CLTN *τ CLTP* τ
Using N subscript to refer to normal and P subscript to refer to patient with polymorphism.
If using same dosing intervals (τ) – terms cancel out
So….
FN *DOSEN = FP *DOSEP
CLTN CLTP

49. Solution: Drug A Normal: F =0.9 CLT= 9 L/hr Dose = 25 mg every 24 hr
Polymorphism : F= CLT =4.75 L/hr
Dose = ? mg / 24 hr

50. Drug B
Normal: F =0.1 CLT= 81 L/hr
Dose = 200 mg every 24 hr
Polymorphism: F= CLT = 73.8 L/hr
Dose = ? mg / 24 hr

51. Real Life Situation
Many cases occur in which we do not have all of this information for a specific drug (ie- values for hepatic or total body clearance) or person (blood flow or enzyme activity in individual).

52. Assessment of Liver function in patients
Want marker/measure of hepatic function which we can use to predict CLH of drugs.
Like creatinine clearance in renal disease
Major difficulty in estimating CLH is that hepatic disease has different effects on different enzyme systems
Numerous pathways of drug metabolism.
Drugs may be metabolized by > 1 enzyme.
NO GOLD STANDARD or parameter to classify patients with hepatic impairment (HI).
- Child-Pugh Index has been used in PK studies to classify patients into very broad categories of hepatic function (normal, moderate liver disease, severe liver disease)
- Liver function tests (ALT, AST) only indicate that liver damage has occurred.

53. Liver function tests 1) Antipyrine 2) Indocyanine Green (ICG)
marker of enzymatic capacity
Hepatic Clearance independent of Q
2) Indocyanine Green (ICG)
High E (E ) dye
Hepatic Clearance related to Q
3) Galactose blood conc.
Quantitative liver function test
Measure galactose conc. 1 hour after administration of 0.5 g/kg.
4) Erythromycin Breath Test
in vivo test to measureCYP3A activity.
IV Admin of 14 C-labeled erythromycin
analyze 14-C in expired breath after 20 min.
*Very specialized tests used experimentally, clinical research studies – not used in general clinical practice.

54. Dosage Considerations in Hepatic Disease
Most liver function tests only indicate that the liver has been damaged; they do not assess the function or CLint of specific enzymes in liver.
Hepatic blood circulation and flow is also difficult & $$$$ to assess in clinical settings.
Hence, patients with hepatic failure (or enzyme deficiencies) are often dosed based on estimations of the remaining liver function (or enzyme activity) and knowledge of the fraction of drug eliminated via that route.

55. Fraction of drug metabolized
[CLH] HI: Hepatic CL in liver disease
[CLH] Norm: Hepatic CL in normal
[ CLT]: Total body clearance
fm: fraction of drug metabolized ( 1-fe)
RL = Remaining liver function
= [CLH] HI/ [CLH] Norm
[CLT]HI = [CLH] HI + [CLR]Norm
[CLT]HI = RL*[ CLT]norm * fm + [CLT]norm* fe
Thinking in Terms of Dose:
DOSEHI = [(RL * fm) + fe ] * DOSEnorm

56. Problem
A novel drug Prostop used to treat prostrate cancer, is excreted primarily through metabolism (95%). In patients in normal hepatic function, the average total body clearance is 62 L/hr, the t½ is 5.5 hours and the normal daily dose is 250 mg every 8 hours.
For patients with severe liver disease with a 50% reduction in hepatic function :
Estimate the clearance and t½ of Prostop
Recommend a daily dosing regimen.

57. Solution Drug: Prostop fraction metabolized (fm) = 0.95
Assume non-metabolized is cleared renally {fe = 0.05}
CLTnorm 62 L/hr
DOSEnorm 250 mg every 8 hours
Patients with liver disease:
50% remaining liver function (RL)
Assume normal renal function
Assume Vd is not affected

58. Drug: fm = 0.95 fe = 0.05 CLTnorm = 62 L/hr Patients: RL = 0.5
i) Estimate Clearance in these patients.
[CLT]HI = [CLH] HI + [CLR]Norm
= { RL*[ CL]norm *fm} + {[CL]norm* fe}

59. ii) Calculate t½ in these patients. CLT = K * V
t ½ = * V /CLT
* 1st need to calculate Vd (not changed from normal)
Normal : t½ = 5.5; CLT = 62 L/hr
Liver failure: CLT = L/hr; t½ = ?

60. iii) Dosage Recommendation
DOSEnorm = 250 mg Q8H = 750 mg/day
* Drug available in 100, 250, 500 mg caps.
DOSEHI = [(RL * fm) + fe ] * DOSEnorm

61. Could also use this method to calculate dose for polymorphisms of enzyme activity when CLint values are unknown & can not be calculated based on CLH.
Consider fraction metabolized by polymorphic enzyme and remaining enzyme activity.

62. Urine Collection Period Amount in urine (mg)
Practice Problem 1
Prezic is a newly marketed antidepressant drug, eliminated by hepatic metabolism and renal excretion. Plasma and urine data was determined following administration of mg IV dose to a 68 kg male subject (45 years old). Assume a liver plasma flow rate of 825 ml/min.
PLASMA DATA (Prezic) :
AUC 0-24 = 256 g*hr/L
AUC 0-inf = g*hr/L
t½ = 3 hr
URINE DATA:
Urine Collection Period Amount in urine (mg)
0-6 hr
6-12 hr
12-24 hr
Calculate CLT, CLr, CLint and ER for
Prezic in this patient.

63. Practice Problem 1b Administration of acebutolol causes a
reduction in hepatic plasma flow
to approximately 650 ml/min.
Estimate the hepatic clearance and t 1/2 in this
Patient if Prezic is taken with acebutolol.
Assume that neither renal clearance or intrinsic
clearance is affected.
A. CLH = ________________ L/hr?
B. t 1/2 = ________________ hr?

64. Practice Problem 2.
On the graph below, draw a representative line (exact numbers not required) depicting the anticipated change in plasma concentration versus time curve for a highly extracted drug when:
liver blood flow is reduced
liver blood flow is increased?
For each line, use a different color or line format
and label the lines accordingly..