Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

Stevison, Faith; Kosaka, Mika; Kenny, Jane R.; Wong, Susan; Hogarth, Cathryn A.; Amory, John K.; Isoherranen, Nina

doi:10.1111/cts.12616

Cited by 20 publications

(61 citation statements)

References 30 publications

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“…In plasma, the fraction of at RA bound is >0.99, [ 11 ] likely bound to albumin [ 1 , 33 ]. Pregnancy is associated with a decrease in albumin concentrations [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…Vitamin A bioactivity is attributed to the metabolite all-trans -retinoic acid ( at RA), while other metabolites such as 13- cis -retinoic acid (13 cis RA), and the downstream metabolite of 13 cis RA, 4-oxo-13- cis -retinoic acid (4oxo13 cis RA) are also present in circulation and tissues in humans [ 2 ]. These metabolites circulate at lower concentrations than retinol [ 9 ] and bind to albumin [ 1 , 10 ] such that <0.001% circulates as the free form [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Plasma Retinoid Concentrations Are Altered in Pregnant Women

et al. 2022

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Vitamin A is vital to maternal–fetal health and pregnancy outcomes. However, little is known about pregnancy associated changes in maternal vitamin A homeostasis and concentrations of circulating retinol metabolites. The goal of this study was to characterize retinoid concentrations in healthy women (n = 23) during two stages of pregnancy (25–28 weeks gestation and 28–32 weeks gestation) as compared to ≥3 months postpartum. It was hypothesized that plasma retinol, retinol binding protein 4 (RBP4), transthyretin and albumin concentrations would decline during pregnancy and return to baseline by 3 months postpartum. At 25–28 weeks gestation, plasma retinol (−27%), 4-oxo-13-cis-retinoic acid (−34%), and albumin (−22%) concentrations were significantly lower, and all-trans-retinoic acid (+48%) concentrations were significantly higher compared to ≥3 months postpartum in healthy women. In addition, at 28–32 weeks gestation, plasma retinol (−41%), retinol binding protein 4 (RBP4; −17%), transthyretin (TTR; −21%), albumin (−26%), 13-cis-retinoic acid (−23%) and 4-oxo-13-cis-retinoic acid (−48%) concentrations were significantly lower, whereas plasma all-trans-retinoic acid concentrations (+30%) were significantly higher than ≥3 months postpartum. Collectively, the data demonstrates that in healthy pregnancies, retinol plasma concentrations are lower, but all-trans-retinoic acid concentrations are higher than postpartum.

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“…In plasma, the fraction of at RA bound is >0.99, [ 11 ] likely bound to albumin [ 1 , 33 ]. Pregnancy is associated with a decrease in albumin concentrations [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plasma Retinoid Concentrations Are Altered in Pregnant Women

et al. 2022

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“…Similarly, Wang and colleagues report in vitro downregulation of CYP3A4 mRNA by carfilzomib in human hepatocytes in vitro, which did not affect midazolam pharmacokinetics in patients with cancer (AUC 0-' ratio [least squares mean (90% geometric CI) 108.2 (94.1-124)]) (Wang et al, 2013). Conversely, it was shown that weak induction of CYP3A-mediated midazolam clearance by the retinoid compounds was indeed predictable based on in vitro studies (Stevison et al, 2019). These studies again highlight the currently unreliable prediction of in vivo DDIs from in vitro data for CYP induction and/or downregulation.…”

Section: Discussionmentioning

confidence: 99%

“…Because there was no effect of multiple doses of 200 mg abemaciclib Q12H on dextromethorphan [AUCR 0.976 (0.805,1.18)], both the in vitro induction and downregulation appear to be false positives. The ability to predict in vivo CYP2D6 induction from in vitro studies is mixed: Sager et al (2017) successfully predicted CYP2D6-mediated DDIs for bupropion based on simultaneous CYP2D6 inhibition and induction, but in vitro CYP2D6 downregulation by retinoids identified by Stevison et al (2019) did not translate into the clinic. The CYP1A2 substrate caffeine exhibited statistically significant increases in AUC, but the analysis was confounded by evidence of noncompliance with the dietary restriction of caffeine.…”

Section: Discussionmentioning

confidence: 99%

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

et al. 2020

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Abemaciclib is an orally administered, potent inhibitor of cyclindependent kinases 4 and 6 and is metabolized extensively by CYP3A4. The effects of abemaciclib on several CYPs were qualified in vitro and subsequently evaluated in a clinical study. In vitro, human hepatocytes were treated with vehicle, abemaciclib, or abemaciclib metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib (M20)]. mRNA levels for eight CYPs were measured using reversetranscription quantitative polymerase chain reaction, and, additionally, catalytic activities for three CYPs were determined. In the clinical study, adult patients with cancer received a drug cocktail containing CYP substrates [midazolam (3A), warfarin (2C9), dextromethorphan (2D6), and caffeine (1A2)] either alone or in combination with abemaciclib. Plasma pharmacokinetics (PK) samples were analyzed for all substrates, caffeine metabolite paraxanthine, and abemaciclib; polymorphisms of CYP2C9, CYP2D6, CYP3A4, and CYP3A5 were evaluated. In vitro, downregulation of CYP mRNA, including 1A2, 2B6, 2C8, 2C9, 2D6, and 3A, by abemaciclib and/or M2 and M20 was observed at clinically relevant concentrations. In humans, abemaciclib did not affect the PK of CYP2D6 or CYP2C9 substrates. Minor statistically significant but clinically irrelevant changes were observed for midazolam [area under the concentration versus time curve from zero to infinity (AUC 0-inf) (13% lower), C max (15% lower)], caffeine [AUC 0-inf (56% higher)], and paraxanthine: caffeine [area under the concentration versus time curve from 0 to 24 hours ratio (was approximately 30% lower)]. However, given the magnitude of the effect, these changes are not considered clinically relevant. In conclusion, the downregulation of CYP mRNA mediated by abemaciclib in vitro did not translate into clinically meaningful drug-drug interactions in patients with cancer. SIGNIFICANCE STATEMENT Despite observations that abemaciclib alters the mRNA of various CYP isoforms in vitro, a clinical study using a drug cocktail approach found no clinically meaningful drug-drug interactions between abemaciclib and a range of CYP substrates [midazolam (CYP3A4), S-warfarin (CYP2C9), dextromethorphan (CYP2D6), and caffeine (CYP1A2)]. This lack of translation suggests greater understanding of mechanisms of CYP downregulation is needed to accurately predict clinical drug-drug interaction risk from in vitro data.

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“…On the one hand, reduced expression of non-specific RA-degrading cytochromes may provide a mechanism for increased at-RA serum levels in clozapine-treated subjects. On the other hand, recent in vitro evidence demonstrates the downregulation of CYP2D6 mRNA upon stimulation with retinoids [ 76 ], which suggests that reduced levels of CYP2D6 in clozapine patients may also be a consequence of increased RA-signaling. The results must, however, be interpreted with caution, particularly because little is known about the role and functional implications of altered blood-cell-based mRNA expression of CYP450 isozymes.…”

Section: Discussionmentioning

confidence: 99%

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

et al. 2020

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The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoidrelated genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

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Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

Cited by 20 publications

References 30 publications

Plasma Retinoid Concentrations Are Altered in Pregnant Women

Plasma Retinoid Concentrations Are Altered in Pregnant Women

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

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