Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC 50 , k inact , and K I values were 10.4 6 1.4 mM, 0.060 6 0.002 min 21 , and 1.13 6 0.12 mM for PRN, and 7.1 6 0.6 mM, 0.10 6 0.01 min 21 , and 1.95 6 0.31 mM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC 50 values of 0.26 6 0.01 mM and 0.22 6 0.03 mM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with k inact and K I values of 0.050 6 0.002 min 21 and 0.40 6 0.06 mM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71-and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24-and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

l-tetrahydropalmatine (l-THP) is a tetrahydroprotoberberine isoquinoline alkaloid that has been used as an analgesic agent in China for more than 40 years. Recent studies indicated its potential application in the treatment of drug addiction. In this study, a sensitive and rapid method using ultra high performance liquid chromatography with MS/MS was developed and validated for simultaneous quantitation of l-THP and its desmethyl metabolites. Enzymatic hydrolysis was integrated into sample preparation to enable the quantitative determination of both free and conjugated metabolites. Chromatographic separation was achieved on an Agilent Poroshell 120 EC-C18 column. Detection was performed by MS in the positive ion ESI mode. The calibration curves of the analytes were linear (r(2) > 0.9936) over the concentration range of 1-1000 ng/mL with the lower limit of quantification at 1 ng/mL. The precision for both intra- and interday determinations was <8.97%, and the accuracy ranged from -8.74 to 8.65%. The recovery for all the analytes was >70% without significant matrix effect. The method has been successfully applied to the urinary excretion study of l-THP in rats. The conjugates were found to be the major urine metabolites of the drug.

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