Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects

Abstract

Background Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb–drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood–brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John’s wort. This investigation evaluated effects of St. John’s wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects. Methods Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John’s wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic–pharmacodynamic modeling. Results St. John’s wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John’s wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John’s wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John’s wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John’s wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John’s wort had no influence on analgesia, cognitive performance, or somatic cognitive–affective effects of fentanyl. Conclusions St. John’s wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John’s wort will likely not respond differently to IV fentanyl for anesthesia or analgesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Intranasal Fentanyl for Intervention-Associated Breakthrough Pain After Cardiac Surgery

“…Compartmental parameter estimates for the fentanyl three-compartment analysis using Loughren priors [ 22 ] are shown in Table 3 and those for the confirmatory analysis using Shafer et al priors [ 23 ] in Table S2 of the ESM. Figure 3 shows satisfactory visual predictive check plots for these PK data.…”

“…Fentanyl priors were sourced from two publications. Loughren and colleagues estimated fentanyl parameters and their variability in a study investigating the impact of St John’s wort on pharmacokinetics [ 22 ]. Shafer and colleagues estimated fentanyl parameters using pooled data during infusion [ 23 ].…”

“…In Group 2, the median %maxSPID on the first postoperative morning after fentanyl 200 µg was at rest 57% (− 261% to 97%, p = 0.259 compared to Group 1), during deep breathing 53% (− 4% to 81%, p = 0.279) and at cough 29% (− 102% to 67%, p = 1.000), and after fentanyl 100 µg on Table 3 Standardised population pharmacokinetic parameter estimates for intranasal fentanyl using Loughren priors [22] BSV between-subject variability, BOV between-occasion variability, CI confidence interval of the structural estimate, F NASAL intranasal bioavailability, T abs1/2 absorption half-life A three-compartment linear disposition model with first-order absorption and first-order elimination was used to analyse concentration-time profiles. Population estimates of clearance (CL), intercompartmental clearances (Q 2 and Q 3 ) and three volumes of distribution the third postoperative morning at rest 0% (− 27% to 97%, p = 0.189), during deep breathing 80% (− 165% to 97%, p = 0.336) and at cough 2% (− 75% to 80%, p = 0.328).…”

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance

“…Successively, it was demonstrated that the induction of CYP3A and P-gp by SJW, in healthy volunteers, depends on hyperforin concentration in the different type of extracts used [28][29][30], and, in particular, it was suggested that a daily dose of 1 mg of hyperforin is a critical cut-off for clinically significant interactions [31]. A recent randomized, double-blind, parallel-arm, clinical trial enrolling 16 healthy volunteers has evaluated the effect of SJW on fentanyl, the latter being metabolized by hepatic CYP3A4 and transported by P-gp [32]. Under these circumstances, the pharmacokinetics and pharmacodynamics of fentanyl do not result affected.…”

Herb–Drug Interactions: Worlds Intersect with the Patient at the Center

“…The following are available online at , Table S1: Pharmacokinetic Pathways for Drugs Implicated in Herb–Drug Interactions Where Herb Was Clinically Studied; Table S2: Findings of Clinical Studies; Table S3: Comparison of Case Reports to Herb–Drug Interaction Checkers; Table S4: Case Report Summaries; Table S5: Materials and Methods of Clinical Studies. (References [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 …”