Physiology‐based pharmacokinetic modelling and experimental data suggest that rifabutin alters dolutegravir kinetics by both P‐glycoprotein induction and concurrent inhibition

Theile, Dirk; Nilles, Julie; Meid, Andreas D.

doi:10.1111/bcp.15740

Cited by 2 publications

(4 citation statements)

References 13 publications

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“…7 ). This finding is in line with our recently published experimental data (rifabutin-mediated inhibition of human Pgp, over-expressed in porcine kidney cells) and a physiology-based pharmacokinetic model of clinical data (rifabutin–dolutegravir interaction) (Theile et al 2023 ), and underlines the potential clinical relevance given the expected drug concentrations in the gut lumen (600 mg rifampicin: approx. 2.9 mM; 300 mg rifabutin: approx.…”

Section: Discussionsupporting

confidence: 90%

Comprehensive in vitro analysis evaluating the variable drug–drug interaction risk of rifampicin compared to rifabutin

et al. 2023

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Compared to rifampicin (600 mg/day), standard doses of rifabutin (300 mg/day) have a lower risk of drug–drug interactions due to induction of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (Pgp/ABCB1) mediated by the pregnane X receptor (PXR). However, clinical comparisons with equal rifamycin doses or in vitro experiments respecting actual intracellular concentrations are lacking. Thus, the genuine pharmacological differences and the potential molecular mechanisms of the discordant perpetrator effects are unknown. Consequently, the cellular uptake kinetics (mass spectrometry), PXR activation (luciferase reporter gene assays), and impact on CYP3A4 and Pgp/ABCB1 expression and activity (polymerase chain reaction, enzymatic assays, flow cytometry) were evaluated in LS180 cells after treatment with different rifampicin or rifabutin concentrations for variable exposure times and eventually normalized to actual intracellular concentrations. In addition, inhibitory effects on CYP3A4 and Pgp activities were investigated. While rifampicin is poorly taken up by LS180 cells, it strongly activates PXR and leads to enhanced expression and activity of CYP3A4 and Pgp. In contrast, rifabutin is a significantly less potent and less efficient PXR activator and gene inducer, despite sixfold to eightfold higher intracellular accumulation. Finally, rifabutin is a potent inhibitor of Pgp (IC50 = 0.3 µM) compared to rifampicin (IC50 = 12.9 µM). Together, rifampicin and rifabutin significantly differ by their effects on the regulation and function of CYP3A4 and Pgp, even when controlled for intracellular concentrations. Rifabutin’s concurrent Pgp inhibitory action might partly compensate the inducing effects, explaining its weaker clinical perpetrator characteristics.

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Section: Discussionsupporting

confidence: 90%

Comprehensive in vitro analysis evaluating the variable drug–drug interaction risk of rifampicin compared to rifabutin

et al. 2023

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“…In summary, there is some evidence that rifampicin can inhibit P-gp. However, we expect rifabutin to cause considerably stronger P-gp inhibition given the data presented here and published previously (Theile et al 2023 ; Nilles et al 2023 ). Accordingly, prospective clinical trials should compare the induction effects and acute P-gp inhibitory actions of rifampicin versus rifabutin, evaluated by proposed P-gp marker compounds such as dabigatran etexilate (Lutz et al 2018a , b ; European Medicines Agency 2023 ).…”

Section: Discussionsupporting

confidence: 82%

“…Our recently published data revealed several new, yet unknown characteristics of rifabutin that at least in part can explain its weaker net perpetrator effects. First, a physiology-based pharmacokinetic model of the simultaneous administration of rifabutin and dolutegravir (P-gp substrate drug) suggested that rifabutin can enhance intestinal absorption of dolutegravir (high maximum plasma concentration, C max ), even in the state of P-gp induction (repetitive daily intake of rifabutin) (Theile et al 2023 ). That implies rifabutin might partly blunt P-gp induction by concurrent intestinal P-gp inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…Second, direct evidence for the proposed rifabutin-mediated P-gp inhibition was obtained in vitro, demonstrating that rifabutin indeed is a considerably more potent inhibitor of P-gp than rifampicin. However, these experiments used cell lines with murine mdr1a/b overexpression (mediated by long-term exposure to doxorubicin) (Theile et al 2023 ) or genetically engineered cell lines with very high overexpression human P-gp (Nilles et al 2023 ). In contrast, there is no data showing rifabutin-mediated P-gp induction and counteracting P-gp inhibition in the same model.…”

Section: Introductionmentioning

confidence: 99%

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Rifabutin but not rifampicin can partly out-balance P-glycoprotein induction by concurrent P-glycoprotein inhibition through high affinity binding to the inhibitory site

Phondeth,

Kamaraj,

Nilles

et al. 2023

Arch Toxicol

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Physiology-based pharmacokinetic modeling suggests that rifabutin can out-balance P-glycoprotein (P-gp) induction by concurrent P-gp inhibition. However, clinical or experimental evidence for this Janus-faced rifabutin effect is missing. Consequently, LS180 cells were exposed to a moderately (2 µM) and strongly (10 µM) P-gp-inducing concentration of rifampicin or rifabutin for 6 days. Cellular accumulation of the fluorescent P-gp substrate rhodamine 123 was evaluated using flow cytometry, either without (induction only) or with adding rifamycin drug to the cells during the rhodamine 123 efflux phase (induction + potential inhibition). Rhodamine 123 accumulation was decreased similarly by both drugs after 6-day exposure (2 µM: 55% residual fluorescence compared to non-induced cells, P < 0.01; 10 µM: 30% residual fluorescence compared to non-induced cells, P < 0.001), indicating P-gp induction. Rhodamine 123 influx transporters mRNA expressions were not affected, excluding off-target effects. Acute re-exposure to rifabutin, however, considerably re-increased rhodamine 123 accumulation (2 µM induction: re-increase by 55%, P < 0.01; 10 µM induction: 49% re-increase, P < 0.001), suggesting P-gp inhibition. In contrast, rifampicin only had weak effects (2 µM induction: no re-increase; 10 µM induction: 16% re-increase; P < 0.05). Molecular docking analysis eventually revealed that rifabutin has a higher binding affinity to the inhibitor binding site of P-gp than rifampicin (ΔG (kcal/mol) = −11.5 vs −5.3). Together, this study demonstrates that rifabutin can at least partly mask P-gp induction by P-gp inhibition, mediated by high affinity binding to the inhibitory site of P-gp.

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Physiology‐based pharmacokinetic modelling and experimental data suggest that rifabutin alters dolutegravir kinetics by both P‐glycoprotein induction and concurrent inhibition

Cited by 2 publications

References 13 publications

Comprehensive in vitro analysis evaluating the variable drug–drug interaction risk of rifampicin compared to rifabutin

Comprehensive in vitro analysis evaluating the variable drug–drug interaction risk of rifampicin compared to rifabutin

Rifabutin but not rifampicin can partly out-balance P-glycoprotein induction by concurrent P-glycoprotein inhibition through high affinity binding to the inhibitory site

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