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Interaksi Farmakokinetika: Dita Marina Lupitaningrum, M.Farm., Apt
Interaksi Farmakokinetika: Dita Marina Lupitaningrum, M.Farm., Apt
FARMAKOKINETIKA
DITA MARINA LUPITANINGRUM, M.FARM., APT
INTERAKSI
FARMAKOKINETIKA
Absorpsi
Metabolisme
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ABSORPSI
DITA MARINA LUPITANINGRUM, M.FARM., APT
KONSEP
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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
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MANAGEMENT
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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.
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CHANGES IN
GASTROINTESTINAL
MOTILITY
• Sebagain besar obat diabsorpsi di
bagian atas usus halus
• Obat yg merubah pengosongan lambung
akan mempengaruhi absorpsi
• Ex:
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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
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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)
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INTERAKSI FARMKOKINETIKA
ABSORPSI
pH
Gastrointestinal
Malabsorption Pembentukan
caused by drugs Chelat/Komples
Induksi/inhibisi
Perub motilitas
drug transporter
GI
protein
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CONTOH
INTERAKSI
TAHAP
ABSORPSI
STOCKLEY’S DRUG INTERACTION
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DISTRIBUSI
DITA MARINA LUPITANINGRUM, M.FARM., APT
INTERAKSI OBAT TAHAP DISTRIBUSI
2. INHIBITION OR INDUCTION OF
FIRST-PASS METABOLISM
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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)
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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??
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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
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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
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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.
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(B) CHANGES IN ACTIVE RENAL TUBULAR 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
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(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
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(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,
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SECTION DIVIDER
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