CYP3A7 drug‐hormone Interactions in the Neonate: Adrenal Insufficiency and Low Birthweight in the HIV infected Neonate caused by Inhibition of CYP3A7 DHEA‐S Oxidation by Ritonavir

Abstract

In the neonate and developing infant, CYP3A7 is the predominant CYP3A isoform and is responsible for the majority of metabolism of CYP3A substrates. However, its primary function is the 16α‐hydroxylation of the endogenous hormone DHEA‐S, which is important for maintenance of hormone homeostasis in the adrenal gland and production of estriol during the third trimester of pregnancy. Low maternal estriol levels have been reported to lead to low birth weight and premature birth. It has been previously reported that cohorts of HIV infected mothers and their newborns on a combined therapeutic regimen of Lopinavir and Ritonavir have increased adrenal insufficiency and low birth weight, as well as substantially elevated levels of DHEA‐S, leading to adverse outcomes in this fragile patient group. Since Ritonavir is a known potent inhibitor of CYP3A4, we hypothesized that it might also be an inhibitor of CYP3A7‐mediated DHEA‐S oxidation and that this inhibition might be responsible for the adrenal insufficiency and low birth weight associated with Lopinavir‐Ritonavir treatment. In order to test this hypothesis, we employed both recombinant CYP enzyme and neonatal human liver microsomes (nHLMs). We observed significant inhibition of CYP3A7 DHEA‐S hydroxylation activity in the presence of Ritonavir with an IC50 of 0.05 μM. Furthermore, Ritonavir displayed time‐dependent inhibition of DHEA‐S oxidation, with a Ki of 0.336 μM and a Kinact of 0.1077 min−1, suggesting that it may be a mechanism based inactivator of CYP3A7. Lopinavir was also capable of inhibiting CYP3A7, albeit to a much lesser extent than Ritonavir with an IC50 of 5.88 μM for DHEA‐S 16α‐hydroxylation, and without the associated time‐dependency. Interestingly, we observed that Lopinavir alone had a lower intrinsic clearance (Clint) rate in nHLMs compared to adult HLMs, suggesting that a pharmacokinetic enhancer adjuvant may not be necessary in this patient population in order to slow drug clearance and maintain efficacy. At a minimum, our results suggest that closer monitoring of the effective dose of the pharmacokinetic enhancer in neonatal HIV therapy may be required in order to prevent significant inhibition of CYP3A7 DHEA‐S oxidation and the associated adverse effects.Support or Funding InformationThis work was supported by the National Institutes of Health, Institute of General Medical Sciences [Grant R01 GM128508‐03] to JNL.