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BACKGROUND: Chronic pain is associated with depression. Self-treatment of depression with herbal over-the-counter medicine St John's wort makes pain patients prone to drug interactions. AIMS: The aim of this study was to assess the potential of St John's wort to alter the CYP3A-mediated metabolism of a mu-opioid receptor agonist, oxycodone. METHODS: The study design was placebo-controlled, randomized, cross-over with two phases at intervals of 4 weeks and was conducted with 12 healthy participants. St John's wort (Jarsin) or placebo was administered t.i.d. for 15 days and oral oxycodone hydrochloride 15 mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John's wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48 h, behavioural and analgesic effects from 0 to 12 h. RESULTS: Following St John's wort administration the oxycodone AUC decreased 50% (p<0.001). Oxycodone elimination half-life shortened from a mean+/-SD 3.8+/-0.7 to 3.0+/-0.4h (p<0.001). The self-reported drug effect of oxycodone as measured by AUEC(0-12) decreased significantly (p=0.004). Differences between St John's wort and placebo phases in cold pain threshold and intensity AUEC(0-12) were not observed. CONCLUSIONS: St John's wort greatly reduced the plasma concentrations of oral oxycodone. The self-reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs)., Methods: An in vitro CYP probe substrate cocktail assay was used to study the inhibitory effects of fifteen kinase inhibitors on CYP2C9, 3A, and 1A2. Then, DDI predictions were performed using both mechanistic static and physiologically-based pharmacokinetic (PBPK) models., Results: Linsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (K i = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (K i = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (K i = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (K I = 26.5 and 400.3 μM, k inact = 0.060 and 0.026 min -1 , respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (K I = 13.9 μM, k inact = 0.018 min -1 ). Mechanistic static models identified possible DDI risks for linsitinib and vatalanib with (S)-/(R)-warfarin, and for masitinib with (S)-warfarin. PBPK simulations further confirmed that vatalanib may increase (S)- and (R)-warfarin exposure by 4.37- and 1.80-fold, respectively, and that linsitinib may increase (R)-warfarin exposure by 3.10-fold. Mechanistic static models predicted a smaller risk of DDIs between kinase inhibitors and apixaban or rivaroxaban. The greatest AUC increases (1.50-1.74) were predicted for erlotinib in combination with apixaban and rivaroxaban. Linsitinib, masitinib, and vatalanib were predicted to have a smaller effect on apixaban and rivaroxaban AUCs (AUCR 1.22-1.53). No kinase inhibitor was predicted to increase edoxaban exposure., Conclusions: Our results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic., Competing Interests: Declaration of competing interest The authors confirm that they do not have any relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

In vitro evidence shows that the acyl- β -D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 μ M. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl- β -D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared with placebo, with ratios of geometric means of 1.02 [ P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 ( P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl- β -D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase ( P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl- β -D-glucuronide were very low compared with its CYP2C8 inhibition constant (ratio ≪ 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. SIGNIFICANCE STATEMENT: The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of cytochrome P450 (CYP) 2C8. Although candesartan acyl- β -D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations., (Copyright © 2024 by The Author(s).)

Background and Objective: Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine., Methods: We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development., Results: Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers., Conclusions: Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine., Competing Interests: Declarations Funding Open Access funding provided by University of Turku (including Turku University Central Hospital). M.W.A. has received funding from University of Turku Graduate School and Finnish Cultural Foundation, Varsinais-Suomi Regional fund. This study was partially funded by state funding for university-level health research to Turku University Hospital (#11147 for M.W.A. and #13821 for T.I.S.) and to HUS Helsinki University Hospital (TYH2016239 for S.P., K.T.O. and V.K; TYH2019300 for J.B.; and TYH2019240 for M.N.), as well as the Sigrid Jusélius Foundation, Helsinki, Finland (M.N.). Competing Interests This study was a non-commercial, investigator-initiated trial and has not received any funding from the industry. The authors have no financial or proprietary interests in any material discussed in this article. Ethics Approval The study protocol was reviewed and approved by approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District (3/2016) and the Finnish National Agency for Medicines (KL no. 4/2016). Consent to Participate All participants provided written informed consent before study participation. Consent for Publication All authors approved this manuscript for publication. Availability of Data Patient-level data for data on file in this manuscript are not available for sharing as there is a reasonable likelihood that individual patients could be re-identified. Further information can be requested from the authors. Author Contributions S.P., K.T.O. and V.K. conceived the idea and designed the study, contributed to the interpretation of the manuscript and gave final approval of the version to be published; M.Ne, J.I.K, J.B. and M.Ni. contributed to data analyses, interpretation of the manuscript and gave final approval of the version to be published; M.W.A. and T.I.S. supported in study design, collected model information and performed simulations and wrote and finalised the manuscript., (© 2024. The Author(s).)

Riboflavin (vitamin B 2 ) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP-inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug-drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20-fold (90% confidence interval, 1.10-1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug-resistance-associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P-glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP- and MRP4-expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1 μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4-mediated efflux clearance of riboflavin (1.2-1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23-1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Time-dependent inhibition of cytochrome P450 (CYP) enzymes has been observed for a few glucuronide metabolites of clinically used drugs. Here, we investigated the inhibitory potential of 16 glucuronide metabolites towards nine major CYP enzymes in vitro. Automated substrate cocktail methods were used to screen time-dependent inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2J2 and 3A in human liver microsomes. Seven glucuronides (carvedilol β-D-glucuronide, diclofenac acyl-β-D-glucuronide, 4-hydroxyduloxetine β-D-glucuronide, ezetimibe phenoxy-β-D-glucuronide, raloxifene 4'-glucuronide, repaglinide acyl-β-D-glucuronide and valproic acid β-D-glucuronide) caused NADPH- and time-dependent inhibition of at least one of the CYPs investigated, including CYP2A6, CYP2C19 and CYP3A. In more detailed experiments, we focused on the glucuronides of carvedilol and diclofenac, which inhibited CYP3A. Carvedilol β-D-glucuronide showed weak time-dependent inhibition of CYP3A, but the parent drug carvedilol was found to be a more potent inhibitor of CYP3A, with the half-maximal inhibitor concentration (IC 50 ) decreasing from 7.0 to 1.1 µM after a 30-min preincubation with NADPH. The maximal inactivation constant (k inact ) and the inhibitor concentration causing half of k inact (K I ) for CYP3A inactivation by carvedilol were 0.051 1/min and 1.8 µM, respectively. Diclofenac acyl-β-D-glucuronide caused time-dependent inactivation of CYP3A at high concentrations, with a 4-fold IC 50 shift (from 400 to 98 µM after a 30-min preincubation with NADPH) and K I and k inact values of >2,000 µM and >0.16 1/min. In static predictions, carvedilol caused significant (>1.25-fold) increase in the exposure of the CYP3A substrates midazolam and simvastatin. In conclusion, we identified several glucuronide metabolites with CYP inhibitory properties. Based on detailed experiments, the inactivation of CYP3A by carvedilol may cause clinically significant drug-drug interactions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ) of atorvastatin (P = 1.2 × 10 -10 ), 2-hydroxy atorvastatin (P = 4.0 × 10 -8 ), and 4-hydroxy atorvastatin (P = 2.9 × 10 -8 ). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC 0-∞ (P = 3.8 × 10 -8 ). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC 0-∞ (P = 3.9 × 10 -8 ). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC 0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10 -11 ) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC 0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10 -5 ) smaller atorvastatin AUC 0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10 -5 ) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.]., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Aims: Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta ( PPP1R3B) rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for GSD as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with GSD., Methods: Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7 ± 9.8 years, BMI 41.3 ± 4.4 kg/m 2 ) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery., Results: The G allele of PPP1R3B rs4240624 was significantly associated with GSD in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with GSD than in those without gallstones. GSD had an effect similar to that of PPP1R3B genotype on minor lipids., Conclusion: The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome., (© 2024 The Authors.)

Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis-free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non-targeted metabolite profiling by liquid chromatography high-resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10 -5 ) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3-O-glucuronide (GDCA-3G; p = 1.2 × 10 -20 for negative and p = 1.7 × 10 -19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G; p = 2.7 × 10 -16 ). In both the RF and GBDT models, the GCDCA-3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA-3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA-3G feature. In GBDT, the second and third strongest associations were observed with the GDCA-3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA-3G and GDCA-3G as robust OATP1B1 biomarkers in human plasma., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Individual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes., Results: Using non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10 -11 ), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10 -4 ), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, - 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision-recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios., Conclusions: These results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug-drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping., (© 2024. The Author(s).)

Aims: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions., Methods: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose., Results: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC 0-∞ ) and peak plasma concentration (C max ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC 0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases., Conclusions: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)