Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol

Abstract

PurposeThe purpose of this study was to determine the 4 -hydroxycholesterol to cholesterol ratio in mothers and neonates at the time of birth and four months post partum.Method 21 mothers and 22 neonates were recruited at the delivery ward at Karolinska University Hospital, Huddinge,Sweden. Blood samples taken from mothers and neonates at birth and four months post partum were analyzed for 4 -hydroxycholesterol and cholesterol. ResultsThe median plasma concentration of 4 -hydroxycholesterol was higher in mothers at delivery (50 ng/mL) compared to healthy non-pregnant women (29 ng/mL). The pregnant women had a higher median cholesterol concentration (6.2 mmol/L) compared to healthy non-pregnant women (4.6 mmol/L) but this could only partly explain the increased 4 -hydroxycholesterol. The major cause is an increased CYP3A activity during pregnancy. The median 4 -hydroxycholesterol/cholesterol ratio•10 4 was elevated in mothers at time of birth compared to non-pregnant women (0.19 and 0.15, respectively) but decreased to 0.15 four months post partum.Neonates had a median 4 -hydroxycholesterol/cholesterol ratio•10 4 (0.19) comparable to adults already at birth, but lower 4 -hydroxycholesterol (12 ng/mL) and cholesterol (1.8 mmol/L) concentrations. ConclusionPregnancy leads to increased CYP3A enzyme activity as determined by the 4 -hydroxycholesterol/cholesterol ratio. Neonates have low 4 -hydroxycholesterol and cholesterol concentrations but similar total CYP3A activity as adults already at birth.

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

“…This was attributed to the low cholesterol values in newborns, which increased fast and even more than doubled in the first 4 months of life. Neonates had a median ratio (0.19) comparable to adults already at birth (Nylen et al, 2011). This ratio did not change during the first 4 months of life.…”

“…Observations in neonates are limited. Nylen et al determined 4b-OHC and 4b-OHC/cholesterol ratio at birth and 4 months PNA in 21 neonates (Nylen et al, 2011). At birth, neonates had lower plasma 4b-OHC than their mother as well as healthy adults.…”

An Exposure‐Response Modeling Approach to Examine the Relationship Between Potency of CYP3A Inducer and Plasma 4β‐Hydroxycholesterol in Healthy Subjects

“…2,3 Due to the importance of drug-drug interactions (DDIs) mediated by CYP3A, it is necessary to identify the effect of a new drug candidate on CYP3A in the early clinical stages of development to guide the study design of the later phase. [7][8][9][10][11][12][13] Rifampicin induces several drug-metabolizing enzymes and has been extensively used as the preferred strong CYP3A inducer in clinical DDI studies. Based on static calculations and/or dynamic predictions, a dedicated DDI study is usually conducted in healthy volunteers to confirm the drug candidate as a victim or a perpetrator of CYP3A.…”

“…Therefore, plasma 4βHC can provide an early opportunity to investigate a potential clinical inducer during first-in-human studies in healthy volunteers and proof-of-concept trials in the target population. [7][8][9][10][11][12][13] Rifampicin induces several drug-metabolizing enzymes and has been extensively used as the preferred strong CYP3A inducer in clinical DDI studies. [13][14][15] The clinical effect of rifampicin on plasma 4βHC has been well documented in literature.…”

“…Furthermore, DDI findings in healthy volunteers are difficult to extrapolate to the target patient population(s), and dose adjustments due to physiological differences are challenging to determine. Therefore, plasma 4βHC can provide an early opportunity to investigate a potential clinical inducer during first‐in‐human studies in healthy volunteers and proof‐of‐concept trials in the target population …”