TUGAS MANDIRI 3

KIMIA MEDISINAL DASAR

Nama : Eugenia Shepany

No.BP : 1911012040

Propranolol

Berdasarkan proses diatas maka dapat diprediksi bahwa propranolol melalui kedua fase
biotransformasi yaitu:

1. Fase I : N-Dealkylation, Ring hydroxylation, oxidation.

2. Fase II : Glucuronidation & Sulphation

Bentuk metabolit aktifnya adalah 4-hydroxypropranolol

Metabolism

Propranolol is initially metabolized by three main pathways: ring oxidation (approximately 33%
of dose), side chain oxidation (20%) and glucuronidation (17%)

Side chain oxidation is a two step process. The first step to n-desisopropylpropranolol is
catalyzed mainly by CYP1A2 with some involvement of CYP2D6. The second step results in
napthoxylactic acid. Candidate genes for the second step were suggested from experiments with
rat liver microsomes, and include monoamine oxidase (MAOA) and mitochondrial aldehyde
dehydrogenase (ALDH2).

Ring oxidation to 4-hydroxypropranolol is primarily catalyzed by CYP2D6. There is some

residual catalysis to 4-hydroxypropranolol in the presence of CYP2D6 inhibitor quinidine, likely
occurring via CYP1A2. Healthy individuals with poor metabolizer (PM) CYP2D6 phenotype
status (as measured by debrisoquine) showed no significant difference in blood concentrations of
propranolol nor propranolol response as measured by exercise heart rate compared to extensive
metabolizers (Ems). However, flux through the pathway did change with CYP2D6 PMs having
increased clearance of napthoxylactic acid and decreased 4-hydroxypropanolol compared to
Ems.

Glucuronidation of propranolol is carried out by UGT1A9, UGT2B4 and UGT2B7 in the liver
and UGT1A10 extrahepatically There was some steroisoform specificity with the S enantiomer
glucuronidated faster than the R enantiomer.
Secondary metabolism of 4-hydroxypropranolol occurs by glucuronidation and sulfation.
SULT1A3 is involved in the sulfation of 4-hydroxypropranololThe enzymes responsible for the
glucuronidation of 4-hydroxypropranolol specifically (as opposed to gluruonidation of the parent
drug) are not reported.