TUGAS 1

Fase 1

1. Oksidasi

Contohnya : asetaminopen melalui reaksi aromatic hidroksilasi menjadi reaktif metabolit penyebab gagal hati,
reaksi fase 2 nya adalah ether glucorinida

Contoh lain : kodein

IBUPROFEN

Gugus isobutil dalam ibuprofen mengandung tiga kelas karbon: dua primer (C3, C3), satu tersier (C2), dan satu
benzilik (C1) (Gambar 3). Seperti yang digambarkan pada Gambar 4, hidroksilasi metabolik fase I terjadi pada
tiga karbon dengan luasan yang bervariasi [17,18,19,20,21,22]. 3-Hidroksiibuprofen selanjutnya dioksidasi
melalui zat antara aldehida menjadi metabolit asam karboksilat. Oksidasi benzilik-karbon menghasilkan
pembentukan alkohol sekunder kiral (1-hidroksiibuprofen). Baik gugus karboksil intrinsik dan yang dihasilkan
secara metabolik dimetabolisme lebih lanjut dalam fase II menjadi konjugat glukuronida. Semua metabolit
ibuprofen tidak memiliki aktivitas farmakologis [20,23].

TOLMETIN

Tolmetin (Figure 4) is a pyrrole acetic acid NSAID. It is metabolized by the hydroxylation of the benzylic methyl
group to the active hydroxymethyl derivative, which is further oxidized to the inactive 5-p-carboxybenzoyl-1-
methylpyrrole-2-acetic acid in rat, monkey, and human [24,25]. Both the intrinsic and metabolically produced
carboxyl groups are further metabolized in phase II to the inactive glucuronide conjugates. The retention of COX-
inhibiting activity by the hydroxymethyl metabolite may indicate an auxiliary pharmacophoric role of the benzylic
methyl group, since the relatively large phenyl group is responsible for the primary pharmacophoric role.

2. Reduksi

Contohnya : kloramfenikol

ACETOHEXAMID
Acetohexamide (Figure 6) is metabolized by (i) reduction of the carbonyl group to give a hydroxy metabolite that
is 2.5 times as active as the parent drug, as well as (ii) stereoselective oxidation of the cyclohexyl ring to trans-4′-
hydroxyacetohexamide, which is inactive as an oral antidiabetic [29,30].

Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and
Pharmacologic Activity
by  Babiker M. El-Haj 1,* and

Samrein B.M. Ahmed 2

1

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, University of Science and Technology of Fujairah,
Fufairah 00971, UAE
2

College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 00971, UAE
*

Author to whom correspondence should be addressed.

Molecules 2020, 25(8), 1937; https://doi.org/10.3390/molecules25081937

Received: 6 February 2020 / Revised: 1 April 2020 / Accepted: 7 April 2020 / Published: 22 April 2020

PROTONSIL
SULINDAC

3. Dasetilasi

Contohnya : Procainamida menjadi N-asetilprocainamid

PROCAINAMID
The arylamine, procainamide (Procanbid®, 44) (Fig. 6) is a type IA antiarrhythmic agent, whose utility has been
moderated by the relatively high incidence of procainamide-induced lupus erythematosus [66,67]. The major
metabolic fate of procainamide in humans involves acetylation of its 10 amino group to afford N-
acetylprocainamide (45) in a reaction catalyzed by the polymorphic N-acetyltransferase (NAT2) [68-71].
Consistent with the metabolic profile, clinical studies have indicated that patients of the rapid acetylator
phenotype require a longer period of time to develop lupus erythematosus than slow acetylators [67]. As a
consequence, N-hydroxyprocainamide (46) and its two electron oxidation product nitrosoprocainamide (47)
that have been observed as metabolites of procainamide in humans are thought to be responsible for the
abnormalities by analogy to the carcinogenic arylamines [71]. These proposals are based on the finding that
[14C]-procainamide but not [14C]-Nacetylprocainamide covalently binds to mouse liver microsomes (NADPH-
dependent) in vitro as well as in vivo [72,73]. The observation that reducing agents prevent covalent binding of
procainamide to hepatic tissue suggests that nitrosoprocainamide (47) may be the ultimate reactive metabolite
[73,74]. The isolation of a stable glutathione (GSH)-based sulfinic acid conjugate 49 indicates that GSH efficiently
scavenges the reactive nitrosoprocainamide to form the initial unstable mercaptal derivative 48 that rearranges
to 49 and thus, prevents covalent binding to hepatic tissue (see Fig. 6) [73,74]. In vitro studies in human liver
microsomes or recombinant P450s have indicated the involvement of CYP 2D6 in procainamide-N-hydroxylation
and the cytotoxic effects of the N-hydroxyprocainamide and nitrosoprocainamide metabolites have been
established in various cell lines and primary cell cultures [75,76]. Recent clinical studies have resulted in the
detailed evaluation of the role of CYP 2D6 in the in vivo metabolism of procainamide in humans [77]. A key
finding in this report included the ability to measure nitroprocainamide (50), the stable sixelectron oxidation
product of procainamide, in extensive CYP 2D6 metabolizers, but none in poor metabolizers. Concomitant
administration of the CYP 2D6 inhibitor, quinidine, prevented the detection of nitroprocainamide in all
individuals further, confirming the isozyme's role in procainamide bioactivation in humans.

file:///C:/Users/USER/Downloads/Kalgutkar-CDM-2002.pdf

4. Deaminasi

Contohnya : Amphetamine menjadi fenilaseton, fase 2 nya dengan reaksi amida glukoronida

AMPHETAMIN
Fase 2

1. Konjugasi dengan sulfat

Contohnya : Acetaminophen, ASPIRIN, METILDOPA

https://www.slideshare.net/pankajsaraswat/metabolism-final

2. Konjugasi dengan glukuronidasi

Contohnya ; morphine

ASAM BENZOAT
ANILIN

3. Thiol