TY - JOUR
T1 - Biotransformation and brain distribution of the anti-COVID-19 drug molnupiravir and herb-drug pharmacokinetic interactions between the herbal extract Scutellaria formula-NRICM101
AU - Chang, Chun Hao
AU - Peng, Wen Ya
AU - Lee, Wan Hsin
AU - Lin, Tung Yi
AU - Yang, Muh-Hwa
AU - Dalley, Jeffrey W.
AU - Tsai, Tung Hu
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2023/9/20
Y1 - 2023/9/20
N2 - The aim of this study was to explore the effects of herbal drug pharmacokinetic interactions on the biotransformation of molnupiravir and its metabolite β-D-N4-hydroxycytidine (NHC) in the blood and brain. To investigate the biotransformation mechanism, a carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate (BNPP), was administered. Not only molnupiravir but also the herbal medicine Scutellaria formula-NRICM101 is potentially affected by coadministration with molnupiravir. However, the herb-drug interaction between molnupiravir and the Scutellaria formula-NRICM101 has not yet been investigated. We hypothesized that the complex bioactive herbal ingredients in the extract of the Scutellaria formula-NRICM101, the biotransformation and penetration of the blood[sbnd]brain barrier of molnupiravir are altered by inhibition of carboxylesterase. To monitor the analytes, ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC[sbnd]MS/MS) coupled with the microdialysis method was developed. Based on the dose transfer from humans to rats, a dose of molnupiravir (100 mg/kg, i.v.), molnupiravir (100 mg/kg, i.v.) + BNPP (50 mg/kg, i.v.), and molnupiravir (100 mg/kg, i.v.) + the Scutellaria formula-NRICM101 extract (1.27 g/kg, per day, for 5 consecutive days) were administered. The results showed that molnupiravir was rapidly metabolized to NHC and penetrated into the brain striatum. However, when concomitant with BNPP, NHC was suppressed, and molnupiravir was enhanced. The blood-to-brain penetration ratios were 2% and 6%, respectively. In summary, the extract of the Scutellaria formula-NRICM101 provides a pharmacological effect similar to that of the carboxylesterase inhibitor to suppress NHC in the blood, and the brain penetration ratio was increased, but the concentration is also higher than the effective concentration in the blood and brain.
AB - The aim of this study was to explore the effects of herbal drug pharmacokinetic interactions on the biotransformation of molnupiravir and its metabolite β-D-N4-hydroxycytidine (NHC) in the blood and brain. To investigate the biotransformation mechanism, a carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate (BNPP), was administered. Not only molnupiravir but also the herbal medicine Scutellaria formula-NRICM101 is potentially affected by coadministration with molnupiravir. However, the herb-drug interaction between molnupiravir and the Scutellaria formula-NRICM101 has not yet been investigated. We hypothesized that the complex bioactive herbal ingredients in the extract of the Scutellaria formula-NRICM101, the biotransformation and penetration of the blood[sbnd]brain barrier of molnupiravir are altered by inhibition of carboxylesterase. To monitor the analytes, ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC[sbnd]MS/MS) coupled with the microdialysis method was developed. Based on the dose transfer from humans to rats, a dose of molnupiravir (100 mg/kg, i.v.), molnupiravir (100 mg/kg, i.v.) + BNPP (50 mg/kg, i.v.), and molnupiravir (100 mg/kg, i.v.) + the Scutellaria formula-NRICM101 extract (1.27 g/kg, per day, for 5 consecutive days) were administered. The results showed that molnupiravir was rapidly metabolized to NHC and penetrated into the brain striatum. However, when concomitant with BNPP, NHC was suppressed, and molnupiravir was enhanced. The blood-to-brain penetration ratios were 2% and 6%, respectively. In summary, the extract of the Scutellaria formula-NRICM101 provides a pharmacological effect similar to that of the carboxylesterase inhibitor to suppress NHC in the blood, and the brain penetration ratio was increased, but the concentration is also higher than the effective concentration in the blood and brain.
KW - Herb-drug interaction
KW - Molnupiravir
KW - NRICM101
KW - Pharmacokinetics
KW - β-D-N4-hydroxycytidine
UR - http://www.scopus.com/inward/record.url?scp=85161690394&partnerID=8YFLogxK
U2 - 10.1016/j.jpba.2023.115499
DO - 10.1016/j.jpba.2023.115499
M3 - Article
C2 - 37302376
AN - SCOPUS:85161690394
SN - 0731-7085
VL - 234
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
M1 - 115499
ER -