Download Project - MSCBIO 2025

Project
Zhaojia Zhang
Background：
Oxycodone is a semi-synthetic opioid and indicated for the treatment of moderate
to severe pain. Marked as Schedule II controlled substance, it possesses an abuse
liability, becoming one of the three most common overdose-involved prescription
opioid. According to FDA drug labeling, concomitant use with CNS depressants can
lead to higher overdose morbidity and mortality because they are all metabolized
primarily by liver through CYP 3A4 enzymes。This combination may result in the
retardation of oxycodone metabolism and therefore prolong the CNS effects caused by
these two drugs.
Here I choose diazepam which belongs to benzodiazepine family, a kind of CNS
depressant as the representative drug to conduct this research. We hope that through
this simulation research, we can see the delay of oxycodone metabolism in the case of
concomitant use.
(1) Oxycodone metabolic pathway:
This figure shows the metabolic pathway of single oxycodone inside the liver.
Oxycodone conduct phase I metabolism mainly through CYP3A4 (47%), obtaining
inactive metabolite noroxycodone. Besides this, 11% of oxycodone is metabolized by
CYP2D6 to oxymorphone. Then we can simplify it as below:
oxycodone
CYP 3A4
kcat1
CYP2D6
kcat2
noroxycodone
oxymorphone
CYP2D6
kcat3
CYP3A4
kcat4
noroxymorphone
k_bind1= [kf1, kr1]
kcat1 = kf1, kr1, kc1]
k_bind2= [kf2, kr2]
kcat2= [kf2, kr2, kc2]
k_bind3= [kf3, kr3]
kcat3= [kf2, kr3, kc3]
k_bind4= [kf4, kr4]
kcat4= [kf4, kr4, kc4]
kf1=1e-5, kr1= 0.05, kc=1e-1
kf2=1e-5, kr2=1e-1, kc=1e-1
kcat2= kcat3= kcat4
(2) Combination of oxycodone and diazepam
I assume that the process:
Oxycodone
Diazepam
kc
CYP3A4
k_bind1
k_bind2
kcat1
noroxycodone CYP2D6
oxyzepam
kcat2
UGT
noroxymorphone
UGT product
Both oxycodone and diazepam are metabolized by CYP3A4 enzyme to noroxycodone
and oxyzepam, respectively. Noroxycodone is further metabolized by CYP2D6 to
noroxymorphone. Oxyzepam enters phase II metabolism via UGT and gets product.
k_bind1= [kf1, kr1]
k_bind2= [kf2, kr2]
k_bin3= [kf3, kr3]
k_bind4= [kf4, kr4]
kcat1= [kf3, kr3, kc1]
kcat2= [kf4, kr4, kc2]
First, we set kf1= 1e-5, the same as (1):
We can see the amount of noroxycodone is less than that in (1) which means the
concomitant use of diazepam can decrease the oxycodone metabolism.
However, if diazepam competitively binds to CYP3A4, the binding rate of oxycodone
to CYP3A4 should decrease as well as bellows.
kf1=1e-6:
kf1=1e-7:
We can see: if the oxycodone binding rate is decreased to 1e-6 and 1e-7, the amount of
metabolite oxycodone is decreased as well. Furthermore, the time of noroxycodone
existing is prolonged which proves that diazepam cause the delay of oxycodone
metabolism.