Are Tacrolimus Pharmacokinetics Affected by Nephrotic Stage?

Medeiros, Mara; Valverde, Saúl; Moral, Irma Del; L, Velásquez-Jones; Hernández, Ana; Castañeda‐Hernández, Gilberto; Reyes, Herlinda; Filler, Guido

doi:10.1097/ftd.0000000000000285

Cited by 5 publications

(2 citation statements)

References 20 publications

(17 reference statements)

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“…One possible explanation for the different outcomes could be a difference in plasma protein binding rates of the two chemicals. Tacrolimus is strongly bound to plasma protein, whereas the plasma protein binding rate of CTX is only approximately 9% [ 21 , 22 ]. With relatively low hepatic extraction ratios, only unbounded tacrolimus and CTX could be eliminated by hepatic CYPs [ 23 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

et al. 2017

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The traditional Chinese medicine Schisandra chinensis has remarkable protective effects against chemical-induced toxicity. Cyclophosphamide (CTX), in spite advances in chemotherapy and immunosuppressive regimes, is prone to cause severe toxicity due to its chloroacetaldehyde (CAA) metabolite produced by CYP3A. Our previous study identified that S. chinensis extract (SCE) co-administration potently decreased CAA production and attenuated liver, kidney and brain injuries in CTX-treated rats. Gomisin A (Gom A) is proved to be one of the most abundant bioactive lignans in S. chinensis with a significant CYP3A inhibitory effect. To find out whether and how Gom A participated in the chemoprevention of SCE against CTX toxicity, the Gom A-caused CYP3A inhibition in vitro as well as the pharmacokinetic interactions between Gom A and CTX in vivo were examined in this study. Using human liver microsomes, a reversible inhibition assay revealed that Gom A was a competitive inhibitor with a KI value of 1.10 µM, and the time- and NADPH-dependent CYP3A inhibition of Gom A was observed in a time-dependent inhibition assay (KI = 0.35 µM, kinact = 1.96 min−1). Hepatic CYP3A mRNA expression experienced a significant increase in our rat model with Gom A administration. This explained why CAA production decreased in the 0.5 h- and 6 h-pretreatment rat groups while it increased in the 24 h- and 72 h-pretreatment groups, indicating a bidirectional effect of Gom A on CYP3A-mediated CTX metabolism. The present study suggested that Gom A participates like SCE in the pharmacokinetic intervention of CTX by blocking CYP3A-mediated metabolism and reducing CAA production, and thus plays an important role in the chemopreventive activity of S. chinensis against CTX toxicity, in addition to the previously recognized protective effects. Also, the combined use of S. chinensis preparation or other drugs containing Gom A as the main component with CTX needed to be addressed for better clinical intervention.

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Section: Discussionmentioning

confidence: 99%

Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

et al. 2017

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“…Given that children with nephrotic syndrome during relapse have low levels of serum albumin, the pharmacokinetics of tacrolimus may be influenced by the nephrotic state. However, one study reported that the pharmacokinetic profiles of tacrolimus were consistent in the remission and relapse stages of nephrotic syndrome in children …”

Section: Discussionmentioning

confidence: 99%

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

Hao

Song

Zhang

et al. 2020

Brit J Clinical Pharma

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Glomerular diseases are leading causes of end‐stage renal disease in children. Tacrolimus is frequently used off‐label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6‐97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8‐89.5%. In a pilot study with paediatric Henoch‐Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin‐C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow‐up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.

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Therapeutic drug monitoring in childhood idiopathic nephrotic syndrome: a state of the art review

et al. 2023

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Are Tacrolimus Pharmacokinetics Affected by Nephrotic Stage?

Abstract: We conclude that Tac PK profiles are unaltered during relapse of nephrotic syndrome.

Cited by 5 publications

References 20 publications

Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

Time- and NADPH-Dependent Inhibition on CYP3A by Gomisin A and the Pharmacokinetic Interactions between Gomisin A and Cyclophosphamide in Rats

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

Therapeutic drug monitoring in childhood idiopathic nephrotic syndrome: a state of the art review

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