Abstract
Background: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation.
Objective: This study aimed to (i) examine the inhibitory effects of TCAs (viz., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing in vitro-in vivo extrapolation (IVIVE) approaches.
Method: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the in vitro system containing 2% BSA. The Ki values were employed to predict the DDI magnitude in vivo by using static and dynamic mechanistic PBPK approaches
Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective Ki values of 91 ± 7.5 and 82 ± 11 μM, 23 ± 1.3 and 14 ± 0.7 μM, 103 ± 5 and 90 ± 7 μM, and 115 ± 5 and 110 ± 3 μM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was <5% for amitriptyline or nortriptyline. PBPK modelling predicted an increase of less than 10% in the morphine AUC due to the inhibition of clomipramine and imipramine in both virtual healthy and cirrhotic populations.
Conclusion: The results suggest that the likelihood of potential clinical DDIs arising from tricyclic antidepressant inhibition on morphine glucuronidation is low.
Keywords: Drug-drug interaction, glucuronidation, IVIVE, morphine, PBPK modelling, tricyclic antidepressants.
[PMID: 8491060]
[http://dx.doi.org/10.3109/03602530903210716] [PMID: 19795925]
[http://dx.doi.org/10.1016/j.pharmthera.2020.107689] [PMID: 32980440]
[http://dx.doi.org/10.1016/j.biocel.2013.02.019] [PMID: 23500526]
[http://dx.doi.org/10.1124/dmd.31.9.1125] [PMID: 12920168]
[http://dx.doi.org/10.1124/dmd.107.019281] [PMID: 18187562]
[http://dx.doi.org/10.1124/dmd.31.9.1086] [PMID: 12920162]
[http://dx.doi.org/10.1111/j.1533-2500.2001.01025.x] [PMID: 17134407]
[http://dx.doi.org/10.2133/dmpk.22.103] [PMID: 17495417]
[http://dx.doi.org/10.1111/j.1600-0773.1994.tb00319.x] [PMID: 7971731]
[http://dx.doi.org/10.1016/j.bcp.2013.06.019] [PMID: 23835420]
[http://dx.doi.org/10.1016/0304-3959(90)91068-T] [PMID: 2087328]
[http://dx.doi.org/10.1124/jpet.110.167916] [PMID: 20484152]
[http://dx.doi.org/10.1016/j.dmpk.2017.10.005] [PMID: 29241692]
[http://dx.doi.org/10.1111/j.1365-2125.2006.02588.x] [PMID: 16542204]
[http://dx.doi.org/10.1124/dmd.111.039727] [PMID: 21551257]
[http://dx.doi.org/10.1016/j.dmpk.2021.100442] [PMID: 34991001]
[http://dx.doi.org/10.1002/psp4.12144] [PMID: 27935268]
[http://dx.doi.org/10.1124/dmd.118.080523] [PMID: 29695616]
[http://dx.doi.org/10.1124/jpet.113.212258] [PMID: 24459244]
[http://dx.doi.org/10.1146/annurev.pharmtox.38.1.461] [PMID: 9597163]
[http://dx.doi.org/10.1038/clpt.1980.140] [PMID: 7389249]
[http://dx.doi.org/10.2165/00003088-199120060-00002] [PMID: 2044329]
[http://dx.doi.org/10.1124/dmd.116.071639] [PMID: 27440861]
[http://dx.doi.org/10.1111/j.2042-7158.1993.tb05694.x] [PMID: 7903373]
[http://dx.doi.org/10.1016/0364-7722(80)90050-8] [PMID: 7433566]
[http://dx.doi.org/10.1002/(SICI)1099-081X(199601)17:1<81:AID-BDD939>3.0.CO;2-5] [PMID: 8991493]
[http://dx.doi.org/10.1002/j.1552-4604.1998.tb04378.x] [PMID: 9597561]
[http://dx.doi.org/10.1007/BF00315289] [PMID: 8436164]
[http://dx.doi.org/10.1111/j.1365-2125.1989.tb05375.x] [PMID: 2719894]
[http://dx.doi.org/10.1007/BF00432768] [PMID: 6813895]
[http://dx.doi.org/10.1016/0165-1781(81)90018-4] [PMID: 6939006]
[http://dx.doi.org/10.1002/cpt1979265600] [PMID: 498703]
[http://dx.doi.org/10.1007/BF00614194] [PMID: 3709631]
[http://dx.doi.org/10.1038/clpt.1983.42] [PMID: 6825388]
[http://dx.doi.org/10.1016/S0140-6736(72)93015-2] [PMID: 4116775]
[http://dx.doi.org/10.1016/S0140-6736(73)90192-X] [PMID: 4118463]
[http://dx.doi.org/10.1002/cpt1978233309] [PMID: 627137]
[http://dx.doi.org/10.1124/dmd.115.066597] [PMID: 26354951]
[PMID: 7628292]
[PMID: 9616184]
[http://dx.doi.org/10.1124/dmd.113.051565] [PMID: 23611809]
[http://dx.doi.org/10.1124/dmd.109.030981] [PMID: 20133892]
[http://dx.doi.org/10.1124/mol.108.048645] [PMID: 18647858]
[http://dx.doi.org/10.1016/j.pharmthera.2023.108459] [PMID: 37263383]
[http://dx.doi.org/10.1124/jpet.106.118216] [PMID: 17237258]
[http://dx.doi.org/10.1124/dmd.106.009340] [PMID: 16565174]
[http://dx.doi.org/10.2165/00003088-199324040-00004] [PMID: 8491058]
[http://dx.doi.org/10.1124/dmd.111.039354] [PMID: 21610127]
[http://dx.doi.org/10.1046/j.1365-2125.2000.00193.x] [PMID: 10792203]
[PMID: 10534321]
[http://dx.doi.org/10.1124/dmd.115.065292] [PMID: 26443648]
[http://dx.doi.org/10.1080/00498254.2022.2132426] [PMID: 36222269]