INTERAKSI

FARMAKOKINETIKA
DITA MARINA LUPITANINGRUM, M.FARM., APT
INTERAKSI
FARMAKOKINETIKA

Absorpsi

Ekskresi Proses Distribusi

Metabolisme

2
ABSORPSI
DITA MARINA LUPITANINGRUM, M.FARM., APT
KONSEP

• Istilah: rate of absorption dan total

amount absorbed
• For drugs that are given long-term, in
multiple doses (e.g. warfarin) the rate of
absorption is usually unimportant,
provided the total amount of drug
absorbed is not markedly altered.
• drugs that are given as single doses,
intended to be absorbed rapidly (e.g.
analgesics such as paracetamol
(acetaminophen)), where a rapidly
achieved high concentration is needed, a
reduction in the rate of absorption may
result in failure to achieve an adequate
effect

4
EFFECTS OF CHANGES IN
GASTROINTESTINAL PH
Dipengaruhi: pKa obat
lipid-solubility
pH of the contents of the gut
Formulasi obat
Absorpsi
Asam
Lebih besar pada keadaan??
salisilat
Asam (pH ↓)

H-receptor
antagonis
Merubah pH lambung  often uncertain, but
some cases the effect can be significant

5
MANAGEMENT

6
ADSORPTION, CHELATION
AND OTHER COMPLEXING
MECHANISMS
• tetracycline + divalent and trivalent
metallic ions (calcium, aluminium,
bismuth and iron)
• to form complexes that are both poorly
absorbed and have reduced antibacterial
effects
• Management
• Separating the doses by 2 to 3 hours
goes some way towards reducing the
effects of this type of interaction.

7
CHANGES IN
GASTROINTESTINAL
MOTILITY
• Sebagain besar obat  diabsorpsi di
bagian atas usus halus
• Obat yg merubah pengosongan lambung
akan mempengaruhi absorpsi
• Ex:

8
INDUCTION OR INHIBITION
OF DRUG TRANSPORTER
PROTEINS
• Ketersediaan hayati oral dari
beberapa obat dibatasi oleh kerja
protein transporter obat
• Difusi obat dialam usus.
• P-glycoprotein
• Drug transporter proteins, which
eject drugs that have diffused across
the gut lining back into the gut.
• Digoxin: substrate of P-glycoprotein
• Drugs that induce this protein:
rifampicin

9
MALABSORPTION CAUSED
BY DRUGS
• Neomycin causes a malabsorption
syndrome, similar to that seen with
non-tropical sprue. The effect is to
impair the absorption of a number of
drugs including (p.745)

10
INTERAKSI FARMKOKINETIKA
ABSORPSI
pH
Gastrointestinal

Malabsorption Pembentukan
caused by drugs Chelat/Komples

Induksi/inhibisi
Perub motilitas
drug transporter
GI
protein

11
CONTOH
INTERAKSI
TAHAP
ABSORPSI
STOCKLEY’S DRUG INTERACTION

1
2
DISTRIBUSI
DITA MARINA LUPITANINGRUM, M.FARM., APT
 INTERAKSI OBAT TAHAP DISTRIBUSI

PROTEIN-BINDING INDUCTION OR INHIBITION OF

INTERACTIONS DRUG TRANSPORTER PROTEINS

Berikatan dengan protein plasma It is increasingly being recognised

 albumin, bersifat Reversible that distribution of drugs into the
brain, and some other organs such
Aktif: free (unbond)
as the testes, is limited by the action
Tgt pada konsentrasi obat dan of drug transporter proteins such as
afinitas ikatan  dpt P-glycoprotein.
berkompetisi dgn obat lain
These proteins actively transport
Drugs can also become bound to drugs out of cells when they have
albumin in the interstitial fluid, and passively diffused in
some, such as digoxin, can bind to
the heart muscle tissue.  Obat yang menghambat prot
pembawa  ↑ uptake obat ke otak
Ex: warfarin, sulfonylureas,  ↑ efektivitas dan eso
phenytoin, methotrexate, And
valproate
15
METABOLISME
DITA MARINA LUPITANINGRUM, M.FARM., APT
 2 Fase:
• Fase I: oksidasi, reduksi & hidrolisis
• Metabolisme = biotransformasi = • Mengubah obat lebih polar
biochemical degradation = • CYP P450, mooamin oksidase
detoxification
• Fase II: coupling with other
• Obat substances (As. Glukoronat)  inaktif
• Sedikit obat diekresi dlm bentuk yg tdk
berubah
• Sebag besar  diubah mjd less lipid-
soluble
• Proses metabolism: serum, ginjal,
kulit dan usus halus, tp paling banyak
dimetabolisme oleh enzim pd
membrane reticulum endoplasma
dalam sel hati
A. CHANGES IN FIRST-PASS METABOLISM

1. CHANGES IN BLOOD FLOW

THROUGH THE LIVER.
• Inhibisi dan induksi enzim (terutama
sitokrom P450 mengubah first-pass
• portal circulation  obat ke hati scr langsung sblm metabolism
didistribusikan melalui aliran darah k seluruh tubuh
• grapefruit juice + CCB
• Few clinically relevant • inhibit the cytochrome P450
isoenzyme CYP3A4, mainly in the
gut, and therefore reduces the
metabolism of oral CCB

2. INHIBITION OR INDUCTION OF
FIRST-PASS METABOLISM

18
B. ENZYME INDUCTION
• Induksi  metabolism ↑  ekskresi↑
• Most in phase I
• Phase II, ex: Rifampisin + zidovudine
• Barbiturat auto induksi
• ↑ enzim mikrosomal
• Dipengaruhi oleh obat dan dosis
 delayed in onset and slow to
resolve
• Solusi: raising the dose of
• requires good monitoring (for drug need
tappering off and may be an overdose
when the drug metabolism has returned
to normal)
19
C. ENZYME INHIBITION
• Inhibisi  ↓ metabolism  ↑ akumulasi pd tubuh
• rapid development of toxicity
• Most in Phase I
• Ex: sildenafil after ritonavir had also been taken for 7 days
• ritonavir inhibits the metabolism of sildenafil by CYP3A4
• valpromide+ carbamazepine
• phase I hydrolytic metabolism, is the inhibition of epoxide hydrolase by valpromide,
which increases the levels of ‘carbamazepine’
• inhibition of carbamazepine glucuronidation by ‘sodium valproate’
• Efek interaksi
• Brp konsentrasi?? Signifikan scr klinik??

20
21
D. GENETIC FACTORS IN
DRUG METABOLISM
• genetic polymorphism
• Perbedaan isoenzim tertentu
• CYP2D6, CYP2C9 and CYP2C19 also show polymorphism, whereas CYP3A4 does no
• Alasan mengapa berbeda efek pd setiap individu
• CYP2D6 ↓ (about 5 to 10% in white Caucasians, 0 to 2% in Asians and black
people)  memtabolisme beta bloker
• slow metabolisers
• CYP2C19 ↓ (6% of Caucasians, 1 to 7.5% of Blacks and 12 to 23% of Oriental
and Indian Asians)  memetabolisme PPI
• slow metabolisers

22
E. CYTOCHROME P450 ISOENZYMES
AND PREDICTING DRUG
INTERACTIONS
• prediksi melalui: in vitro tests with
human liver enzymes
• ciclosporin is metabolised by CYP3A4,
and rifampicin is a known potent
inducer of this isoenzyme, whereas
ketoconazole inhibits its activity, so
that it comes as no surprise that
rifampicin reduces the levels of
ciclosporin and ketoconazole
increases them.
• Ingat: satu obat dpt dimetabolisme
oleh lebih dr satu cytochrome P450
isoenzyme
23
EKSKRESI
DITA MARINA LUPITANINGRUM, M.FARM., APT
EKSKRESI
• Inhalasi, empedu, dan urin
• Dipengaruhi: fluid pH, with active
transport systems
• and with blood flow to the kidney can
alter the excretion of other drugs
(A) CHANGES IN URINARY PH
• Bentuk: non-ionised lipid soluble
 dpt berdifusi melalui membrane
lipid pd sel tubulus
• tgt pKa & pH urine.
• Sedikit obat yg terpengaruh pH urin
• Contoh:‘analgesic-dose aspirin’,
(p.151)
• In cases of overdose, deliberate
manipulation of urinary pH has been
used to increase the removal of drugs
such as methotrexate and salicylates.

26
(B) CHANGES IN ACTIVE RENAL TUBULAR EXCRETION

Obat dgn sistem transport aktif yang sama pada tubulus

ginjal can compete with one another for excretion.

Contoh:
• probenecid ↓ ekskresi penisilin dan obat lain  melalui organic
onion transporters (OATs).
• Probenecid possibly also inhibits some of the ABC transporters in the
kidneys. The ABC transporter, P-glycoprotein, is also present in the
kidneys, and drugs that alter this may alter renal drug elimination

27
(C) CHANGES IN RENAL
BLOOD FLOW
• Aliran darah melalui ginjal sebagian
dikontrol oleh produksi prostaglandin
sbg vasodilator
• Sintesis prostaglandin dihambat 
ekskresi obat ↓
• Ex: litium dan NSAID

28
(D) BILIARY EXCRETION AND THE ENTERO-HEPATIC SHUNT
1. Enterohepatic recirculation
• obat diekskresikan dalam empedu, baik tidak berubah atau terkonjugasi (misalnya
sebagai glukuronida)  untuk membuatnya lebih larut dalam air.
• Beberapa konjugat dimetabolisme menjadi senyawa induk oleh flora usus dan kemudian diserap
kembali.
• Proses daur ulang ini  memperpanjang masa tinggal obat di dalam tubuh
• jika flora usus berkurang dengan adanya antibakteri, obat tersebut tidak didaur
ulang dan hilang lebih cepat.
• Ex: kegagalan kontrasepsi hormonal yang dapat disebabkan oleh penggunaan
penisilin atau tetrasiklin secara bersamaan,

29
30
 SECTION DIVIDER
Lorem ipsum dolor sit amet, consectetuer adipiscing elit. Maecenas porttitor
congue massa. Fusce posuere, magna sed pulvinar ultricies, purus lectus
malesuada libero, sit amet commodo magna eros quis urna.

31