Variability of Hepatic Drug Metabolism & Dosage Adjustment

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.

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.

HEPATIC DISEASE

2 Major types of Liver DiseaseCirrhosis- 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.

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

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

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.

Hepatic Clearance

LIVER

Blood IN Blood OUT

25% Hepatic Artery

75% Portal Vein

Bile

Hepatic Vein

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)

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

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

Drug can be removed by liver in two manners: 1) 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.

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!

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

Bioavailability (F)

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 400 mL/min

was calculated.

Q1. What is the predicted hepatic ER of Zee® ?

ER = CLH / QH

-

Q2. Assuming complete intestinal absorption, what is the equivalent oral dose of Zee® ?

fer = 1-ER

Q3. If the intestinal absorption of Zee® is incomplete (70%) - what

oral dose is required? F = fdis x fabs x fer

Not always so simple…..

Hepatic extraction is dependent on

several factors that can change

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

Calculation of ER based on mechanism

Capacity& Affinity

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)

Other important equations describing this relationship:

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

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

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 > 0.7Very efficiently removed from liver.

Low: ER< 0.3Low efficiency in extraction

Intermediate ER 0.3 - 0.7 ****This an arbitrary division of groups –

there is no absolute ranking system.

Typical drug examples

High ER : Verapamil, lidocaine, propranolol,

nitroglycerin, cocaine, morphine

Intermediate ER:Aspirin, QuinidineNortriptyline

Low ER:Antipyrine, NSAIDs, Diazepam,Erythromycin, PhenytoinTheophylline, Warfarin

* Low ER does not mean it is not metabolized.

Impact of variability in Q and enzyme function on

Hepatic Clearance (CLH)

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 )

CLH = Qh * CL int_

CLint + Qh

Low Extracted Drugs

(ER<0.3)

Qh >> CL int

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

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.

Dosage Route

1) IV 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

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

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

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 30 0.15 2.31 B 30 1.35 0.26

• 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

Solution:

- (CO by 40%) then Q by 40%

- Assume CL int is unchanged

i) Calculate original CL int

- based on original values of Q & CLH.

ii) Determine CLH

use new Q and original CL int

iii) Determine t½ using new CLT

(CLT = CLH)

- assume V not changed

iv) Calculate ER

- use new CLH and new Q

v) Calculate fer using new ER

Summary of Problem Set

Original 40% Qh

Drug AClint L/min

Low E

0.167 0.167

CLH L/min 0.15 0.14

F 0.9 0.84

t½ hr 2.3 2.5

Drug BCLint L/min

High E

13.5 13.5

CLH L/min 1.35 0.84

F

t½ hr

0.1

0.26

0.06

0.41

ER = 0.1 ER = 0.9

LIVER BLOOD FLOW

IV

PO

fer

CLH

↑ t½

CLH

↑ t½

High ER: fer Qh / CL int

Changes in Enzyme Activity. Problem –part BTwo 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 30 0.15 2.31

B 30 1.35 0.26• 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 ).

Solution :

• Assume only CLint changes,

- no change in Q.

i) Calclulate original CL int .

ii) Calculate new CL int .

Polymorphism: 50% CL int

iii) Determine CLH

- use new CL int and original Q

CLH = Qh * CL int_

CLint + Qh

iv) Determine t1/2 using new CLT

(CLT = CLH)

- assume V not changed

v) Calculate ER using new CLH - with original Q

vi) Calculate fer

Summary of Problem Set

Original 50% Clint

Drug AClint 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 BCLint L/min

High E

13.5 6.75

CLH L/min 1.35 1.23

F

t½ hr

0.1

0.26

0.18

0.28

ER = 0.1 ER = 0.9

INTRINSIC CLEARANCE

IV

PO

CLH

↑t½

FCLH

↑t½

High ER: fer Qh / CL int

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.

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).

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

Solution: Drug A

Normal: F =0.9 CLT= 9 L/hr

Dose = 25 mg every 24 hr

Polymorphism : F= 0.95 CLT =4.75 L/hr

Dose = ? mg / 24 hr

Drug B

Normal: F =0.1 CLT= 81 L/hr

Dose = 200 mg every 24 hr

Polymorphism: F= 0.18 CLT = 73.8 L/hr

Dose = ? mg / 24 hr

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).

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.

Liver function tests

1) Antipyrine marker of enzymatic capacity

Hepatic Clearance independent of Q

2) Indocyanine Green (ICG)High E (E 0.7-0.9) 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 Testin 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.

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.

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

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.

SolutionDrug: 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

Drug: fm = 0.95 fe = 0.05 CLTnorm = 62 L/hrPatients: RL = 0.5

i) Estimate Clearance in these patients.

[CLT]HI = [CLH] HI + [CLR]Norm

= { RL*[ CL]norm *fm} + {[CL]norm* fe}

ii) Calculate t½ in these patients.

CLT = K * V

t ½ = 0.693 * V /CLT

* 1st need to calculate Vd (not changed from normal)

Normal : t½ = 5.5; CLT = 62 L/hr

Liver failure: CLT = 32.55 L/hr; t½ = ?

iii) Dosage Recommendation

DOSEnorm = 250 mg Q8H = 750 mg/day

* Drug available in 100, 250, 500 mg caps.

DOSEHI = [(RL * fm) + fe ] * DOSEnorm

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.

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 10 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 = 256.2 g*hr/L t½ = 3 hr URINE DATA:

Urine Collection Period Amount in urine (mg)

0-6 hr 0.489 6-12 hr 0.122 12-24 hr 0.031

Q. Calculate CLT, CLr, CLint and ER for Prezic in this patient.

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?

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:

a) liver blood flow is reducedb) liver blood flow is increased?

0.1

1

10

100

0 5 10 15 20 25 30

Time

Cp

For each line, use a different color or line formatand label the lines accordingly..

Practice Problem 2.