Neonatal abstinence syndrome: comparing the hepatic metabolism of addictive medicines in vitro in the fetus, neonate and adult female
Angeli, Mia.
2018
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Abstract: Neonatal abstinence syndrome (NAS) is defined as neonatal withdrawal
symptoms due to antepartum maternal substance abuse. Substances that are most likely to
cause NAS are opioids, alcohol and central nervous system (CNS) stimulants or depressants,
such as cocaine and benzodiazepines, respectively. Opioid addiction in adults as well as
neonates is treated with methadone or buprenorphi... read morene. In severe maternal addiction and
neonatal withdrawal cases, morphine is administered as an additive to methadone or
buprenorphine. Mothers who are on methadone or buprenorphine treatment are often found to
have plasma traces of alprazolam, a common benzodiazepine prescribed for the treatment of
anxiety. However, the in vitro metabolism of these drugs, either alone or when taken
together, has never been well established in fetuses or neonates. Here, we analyze the
activity of methadone, buprenorphine, morphine, and alprazolam in fetal, neonate and adult
female livers. Since the cytochrome P450 3A enzymes (CYP3A4 and CYPA5) are common and major
routes of metabolism for these drugs, the resulting metabolite of each can be measured to
assess the activity. This was done by in vitro incubations with human liver microsomes
(HLM) from adult females (20-75 years old) and neonates (male and female, 13 days - 11
months old). The metabolites were identified by high-performance liquid chromatography
(HPLC). We found there was no significant difference in alprazolam, buprenorphine or
methadone metabolite formation rate between adults and neonates. Morphine showed inhibition
of alprazolam metabolite formation at high concentrations in both female adult and neonatal
liver microsomes. We also saw high variability between the individual microsomes and
performed a multiple linear regression analysis to determine if age, CYP content, and
alcohol or cigarette use could be responsible for this variability. From these analyses,
CYP content was a significant variable for predicting metabolite formation in all groups
except neonates in 4-hydroxyalprazolam (4-OHALP) and
2-ethylidene-1,5-dimethyl-3,3-dipehnylpyrrolidine (EDDP) production. Additionally,
norbuprenorphine (NBUP) and EDDP formation rate was partially related to alcohol use in
adult females. From these results, we can conclude: 1) the metabolite formation rate
differences of 4-OHALP, BUP, and EDDP between adult females and neonates are not predictors
of neonatal abstinence syndrome onset, but in vitro studies with fetal microsomes still
need to be done and 2) the interaction between morphine and alprazolam occurs at a
concentration too high to be of pharmacokinetic importance, but there may be an underlying
pharmacodynamic mechanism leading to additive effects.
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: David Greenblatt.
Keyword: Pharmacology.read less - ID:
- 8910k5726
- Component ID:
- tufts:26031
- To Cite:
- DCA Citation Guide EndNote
