order of kinetics, adme

Order of Kinetics, ADMEOrder of Kinetics, ADME

SaedGF, BPharm - GSU1

Kinetics of Absorption

FirstFirst--order absorptionorder absorption

First-order absorption means the absorption rate is proportional to the amount of drug at the absorption site.

Typically this means that the absorption rate is higher immediately after the dose is given and the rate then decreases as drug is absorbed.


after the dose is given and the rate then decreases as drug is absorbed.

The fractional rate of decline is constant for a first-order process.

The oral absorption of drugs often approximates first orderkinetics, especially when given in solutionsolution..

Zero-order absorption process

Sometimes, a drug is absorbed at essentially a constantrate.

In zero-order absorption process, the fractional rate


In zero-order absorption process, the fractional rateincreases with time, because the rate is constant butthe amount remaining decreases.

This can be achieved by a constant rate intra-venous infusion. It can also be approximated by somekinds of oral dosing.

Kinetics of Kinetics of metabolismmetabolismFirst-order kinetics: The rate of drug metabolism is directly

proportional to the concentration of free drug.

This means that a constant fraction of drug ismetabolized per unit of time.

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Zero-order kinetics: As the amount of drug rises in the plasma,

certain processes that have limited capacitybecome saturated (limited amount of enzymeseven if dose increases).

Example: Aspirin, EthanolEthanol, and Phenytoin

Kinetics of Kinetics of eliminationelimination

First Order Elimination

For most drugs, the rate of elimination from the body isproportional to the amount of drug present in the body (AB).

This type of elimination kinetics is called first-order elimination or

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This type of elimination kinetics is called first-order elimination orkinetics

The elimination rate constant (kel) is used to denote how quicklydrug serum concentrations decline in a patient.

FirstFirst--orderorder eliminationelimination

The rate of elimination of the drug that follows first orderelimination can be described as:

Elimination rate = dA/dt = - k A , where k is the first-order rate constant.

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With first order elimination,

Elimination rate is dependent on the concentration of A present inthe body.

Constant fraction of drug will be removed (e.g. 10% per hour)

if 1000 mg of a drug is administered and the drug follows firstif 1000 mg of a drug is administered and the drug follows first--order eliminationorder elimination

Time after drug

administration (hrs)

Amount of drug in

body (mg)

Amount of drug Amount of drug

eliminated over eliminated over

preceding hour (mg)preceding hour (mg)

Fraction of drug Fraction of drug


preceding hourpreceding hour

0 1000 __ __

1 850 150150 00..1515

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150150 00..1515

2 723 127127 00..1515

3 614 109109 00..1515

4 522 9292 00..1515

5 444 7878 00..1515

6 377 6767 00..1515

ZeroZero--order eliminationorder elimination

If large amount of drug is administered, then order ofelimination process of the drugs will change from a first-orderprocess to a zero-order process. Example: phenytoin

With zero order elimination

The amount of drug eliminated does not change with AB

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The amount of drug eliminated does not change with AB

The fraction removed varies

The rate of elimination of the drug that follows zero order eliminationcan be described as:

elimination rate = dA/dt = - k*, where k* is the zero-order rate constant

IIf f 1000 mg of a drug is administered and the drug follows 1000 mg of a drug is administered and the drug follows zerozero--order order eliminationelimination

Time after drug

administration

(hrs)

Amount of drug in

body (mg)

Amount of drug Amount of drug


preceding hour (mg)preceding hour (mg)

Fraction of drug Fraction of drug

eliminated over preceding eliminated over preceding

hourhour

0 1000 __ __

1 850 150150 00..1515

11/8/2015CLICAL PHARMACOKINETICS Solomon A., lecturer CHS MU

10

1 850 150150 00..1515

2 700 150150 00..1818

3 550 150150 00..2121

4 400 150150 00..2727

5 250 150150 00..3838

Plots of zero and first order eliminationPlots of zero and first order elimination

First-order kinetics (log y-axis)Zero-order kinetics (linear y-axis)

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First-order kinetics (linear y-axis)

First-order kinetics (log y-axis)Zero-order kinetics (linear y-axis)

Zero Order 1st Order

Half-Life

Half-life is the time taken for the drug concentration to fall to one half of its original value

Plasma half life generally, it is measured by –

The time ….

To decline the plasma concentration of a drug to…. 50% from the peak plasma concentration (PPC / Tmax)


the peak plasma concentration (PPC / Tmax)

Time to decline conc. from 100 to 50 = 2 hr

So, t1/2 of this drug is 2 hr

Generally, a drug will be completely eliminated after 6 half lives After 1 half-life the conc. will be 50%

After 2 half-lives it will be 25%

After 3 half-lives 12.5% and

After 4 half-lives 6.25%





Generally, a decline to 6.25% will usually be far below the therapeutic threshold

For this reason it is usually said that drugs no longer have a pharmacological effect 4 half-lives after the last dose

Clearance (CLClearance (CL))

The clearance (CL) of a drug is the theoreticaltheoretical volumevolume ofofplasmaplasma fromfrom whichwhich drugdrug isis completelycompletely removedremoved inin unitunittimetime.

Mathematically, clearance is the divisiondivision ofof thethe raterate ofofeliminationelimination andand plasmaplasma concentrationconcentration (C(Cpp)).Thus

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eliminationelimination andand plasmaplasma concentrationconcentration (C(Cpp)).Thus

)L

mg(C

)h

mg(n eliminatio of RateCL

p

Bel A . k elimin of Rate

d

p

V C

A . elel kkCL

Clearance…Clearance…

Drugs can be cleared from the body by many differentmechanisms, pathways, or organs, including hepaticbiotransformation and renal and biliary excretion.


Renal clearance = rate of elimination by kidney

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CL total = CL renal + CL hepatic + CL pulmonary +CL others

Renal clearance = rate of elimination by kidney

C

Hepatic clearance = rate of elimination by liver

C

Other organ clearance = rate of elimination by organ

C


For an agent removed primarily by the kidneys, renal clearance(Clr) makes up most of the total body clearance.

For a drug primarily metabolized by the liver, hepatic clearance

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For a drug primarily metabolized by the liver, hepatic clearance(Clm) is most important.

Let’s consider a single organ, kidneys and Q (mL/minute) which isblood flow through the organ, Cin , the drug Conc. in the bloodentering the organ and Cout , the drug Conc. in the exiting blood


Hence an organ's ability to remove a drug (extraction ratio, E) canbe measured by relating Cin and Cout.

outin

C

CCE


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inCE

• If Cout = 0, the drug will be totally removed and the E will be 1.

• If Cout = Cin, there is no drug removal and the E will be 0.

• E generally lies somewhere b/n 0 and 1

Clearance…Clearance… Therefore , The drug clearance of any organ is determined by

blood flow and the extraction ratio:

OOrganrgan clearanceclearance == bloodblood flowflow xx extractionextraction ratioratio == QQ EE

In general, Organ In general, Organ clearance is clearance is high when high when the blood flow the blood flow


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In general, Organ In general, Organ clearance is clearance is high when high when the blood flow the blood flow and the extraction ratio are and the extraction ratio are high. high.

Reading Assignment

Design and Optimization of Dosage Regimen

Variable Dose

Fixed Dose

Optimization of Dosage Regimen

Loading Dose

Maintenance Dose


Maintenance Dose

Steady State Concentration