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1.
Basic Clin Pharmacol Toxicol ; 128(3): 525-533, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33248001

RESUMO

Tacrolimus is important for immunosuppression in kidney transplantation. In this historical cohort and in vitro study, we evaluated the changes in tacrolimus pharmacokinetics early after living donor kidney transplantation and the effects of interleukin (IL)-6 on cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) expression. In the historical cohort study, 22 patients who met the inclusion criteria were classified into CYP3A5 expressors and non-expressors (n = 16 and 6, respectively). The blood tacrolimus concentration per dose ratio (C/D) temporarily increased post-kidney transplantation on days 3-4 only in CYP3A5 non-expressors. The effects of IL-6 on CYP3A4 and CYP3A5 expression were also investigated in vitro using HepG2 and Caco-2 cells. IL-6 induced a significant concentration- and time-dependent decrease in CYP3A4 and CYP3A5 expression in both cells. The mean CYP3A4 expression level at 12 hours after IL-6 exposure (% of 0 hour) was 44.0 and 62.6 in HepG2 and Caco-2 cells, respectively, whereas the CYP3A5 expression level was 30.7 and 52.4, respectively. We hypothesize that CYP3A5 non-expressors might exhibit a temporary decrease in the oral clearance of tacrolimus via an increase in serum IL-6 concentrations early after kidney transplantation. These results may help develop strategies to improve kidney transplant outcome.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/genética , Interleucina-6/farmacologia , Transplante de Rim , Doadores Vivos , Tacrolimo/farmacocinética , Adulto , Idoso , Células CACO-2 , Citocromo P-450 CYP3A/fisiologia , Feminino , Células Hep G2 , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade
2.
Pharmacology ; 101(3-4): 176-183, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29353278

RESUMO

Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC50 value of (S)-lansoprazole against hOAT3-mediated transport of [3H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.


Assuntos
Lansoprazol/química , Lansoprazol/farmacologia , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/farmacologia , Interações Medicamentosas , Estrona/análogos & derivados , Estrona/farmacologia , Células HEK293 , Humanos , Rim/metabolismo , Metotrexato/farmacologia , Proteína 1 Transportadora de Ânions Orgânicos/antagonistas & inibidores , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Pemetrexede/farmacologia , Probenecid/farmacologia , Estereoisomerismo , Ácido p-Aminoipúrico/farmacologia
3.
Drug Metab Dispos ; 44(10): 1543-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27465369

RESUMO

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.


Assuntos
Antagonistas do Ácido Fólico/farmacologia , Testes Hematológicos , Rim/efeitos dos fármacos , Lansoprazol/farmacologia , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Pemetrexede/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Interações Medicamentosas , Feminino , Antagonistas do Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/efeitos adversos , Células HEK293 , Humanos , Rim/metabolismo , Lansoprazol/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Estudos Retrospectivos
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