BAHAN AJAR UNTUK TOPIK MINGGU KE- 6

Topic 6 : Pharmacokinetic Linier and Non Linier

MATA KULIAH :

FARMAKOKINETIKA

Disusun oleh PJMK :

M.M. Farida Lanawati Darsono, S.Si.,M.Sc

Semester Genap
Tahun Akademik : 2021-2022

Universitas Katolik Widya Mandala Surabaya

Fakultas Farmasi

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 Topic 6 : Pharmacokinetic Linier and Non Linier
Objectives:
To understand the schemes and differential equations associated with nonlinear pharmacokinetic
models
• To understand the effect of parallel pathways
• To estimate the parameters Km and Vm
• To design appropriate dosage regimen for drugs with nonlinear elimination

Pustaka tambahan :
https://slideplayer.com/slide/7688300 = Quantitative
Pharmacokinetics - Non Linier Pharmacokinetics by Dr Charlet Tan

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 Review of Linear Pharmacokinetics

i.v.
i.v.
bolus
bolus
100

Log C
M
Log C

10 normalized
M
by dose
1 mg
1 M
10 mg 100
1 mg mg
1h
time
1h time
 Drug plasma concentrations are proportional to the dose
Drug plasma concentration-time profiles are superimposable when normalized
to the dose..

Review of Linear Pharmacokinetics

p. o. p. o.
Log C
Log C

2.5 M normalized
0.5 M by dose
25 mg 0.1
M
0.1 M 1
5 mg
1 mg mg
tmax time
tmax time
 Drug plasma concentrations are proportional to the dose.
 tmax remains unchanged.
Drug plasma concentration-time profiles are superimposable when normalized to
the dose.

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 Nonlinear Pharmacokinetics

i.v. bolus i.v.

800 M bolus
100 mg
Log C

Log C
normalized
20 M
by dose 8 M
10 mg
2 M
1 M
1
1 mg M 100
1 mg 10 mg mg
1h 1h
time time
 Drug plasma concentrations are not proportional to the dose.
 Drug plasma concentration-time profiles are not superimposable when
normalized to the dose.
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Nonlinear Pharmacokinetics

p. o. p. o.
10 M
Log C

M normalized
Log C

1 M

1 M by dose
0.5
M
100 mg 1 mg
0.1 M

10 mg 10 mg
100
1 mg mg
time time
 Drug plasma concentrations are not proportional to the dose.
 tmax may or may not change.
Drug plasma concentrations are not superimposable when normalized to
the dose.

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Common Sources for Nonlinear Pharmacokinetics

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Linear vs. Nonlinear Pharmacokinetics

Linear Nonlinear
(dose-independent) (dose-dependent)

 ADME all obey first-order  at least one of the ADME

kinetics. processes is saturable.

 PK parameters (CL, V, F, Ka,  ≥1 PK parameters are dose-

and t1/2) are constant. dependent.

 AUC is directly proportional to  AUC is disproportional to the

the dose. dose.

 Concentration vs. time profile  Concentration vs. time profile is

is superimposable for all doses. not superimposable for different
doses.

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 e. g. - limited dissolution/solubility in the GI tract

normalized
to the dose - Griseofulvin is poorly
water-soluble (10
mg/L).
- Less proportion of the
drug is being dissolved
and absorbed with the
higher dose.
- F decreases as the
dose increases.
- tmax remains the same.

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e. g. - Saturable transport across the intestinal epithelium

375 mg - Amoxicillin is actively transported by

peptide transporter in the small
750 mg
intestine.
- The active transport becomes
saturated as the dose increases.
- F decreases as the dose increases.
1500 mg - tmax remains the same.
3000 mg

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 e. g. - Saturable first-pass metabolism

- Nicardipine is metabolized by CYP3A4 in the intestinal epithelium and

hepatocytes.
- First-pass metabolism is saturated as the dose increases.
- F increases as the dose increases.

e. g. - Saturable first-pass metabolism

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 - saturable plasma protein binding
- AUC and Cp of
trandolaprilat do not
increase proportionally with
D; Cp does not
accumulate with multiple
doses.
- As the dose increases,
binding to ACE
(angiotensin-converting
enzyme) in plasma is
saturated.
- Trandolaprilat is elminated
by glomerular filtration
CLR= fu GFR
2 g/day - As fu increases with higher
Cp, CLR increases.

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When concentration is about lower than 7

e. g. - capacity-limited renal excretion mg/L, it could be linear. Since clearance is
linear. But once it gets above 7, the
clearance rises, which makes it non-linear.
CLinulin
= GFR
p.o. 30-80 mg
When Cp above
10 mg/L starts
to saturate renal
reabs of Vit C.

i.v. 1.5-6 g

- Vitamin C is reabsorbed from urine by active transporter.

- Tubular reabsorption becomes saturated as Cp increases, i.e. as Cp increases,
CLreabsorption (= Ratereabsorption /Cp) decreases.
- ClR (=fu GFR –CLreabsorption) approaches GFR (fu=1) as Cp increases.
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