In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone

McCune, Jeannine S.; Hawke, Roy L.; LeCluyse, Edward L.; Gillenwater, Heidi H.; Hamilton, Geraldine A.; Ritchie, James C.; Lindley, Celeste

doi:10.1067/mcp.2000.110215

Cited by 147 publications

(124 citation statements)

References 25 publications

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“…We hypothesize that the centre effect is related to steroid use and that continuous therapy leads to an induction of CYP enzymes and higher tacrolimus CL/F. Various studies have demonstrated an induction of CYP3A enzymes by corticosteroid therapy [42][43][44]. Although controversial, studies have identified corticosteroid therapy as a significant factor towards tacrolimus CL/F [9,27,[45][46][47].…”

Section: Figurementioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

151

163

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Patients with low tacrolimus troughs are at a higher risk of rejection while those with high troughs are at an increased risk for toxicity. Therefore, achieving the therapeutic range is important.• CYP3A5 genotype and days post transplant have been previously shown individually to be associated with tacrolimus troughs.WHAT THIS STUDY ADDS• This paper presents the first dosing model for tacrolimus using a combination of genetic and clinical factors in adult kidney transplant recipients. It was developed from one of the largest tacrolimus pharmacogenetic studies conducted to date (681 subjects and 11 823 trough concentrations).• We found that CL/F was significantly influenced by days post transplant, CYP3A5 genotype, transplantation at a steroid sparing centre, recipient age and the use of a calcium channel blocker.• Our large sample size enabled us to define the distinct differences in tacrolimus CL/F between three CYP3A5 genotype groups (*1/*1, *1/*3 and *3/*3).• This study is an important step towards using pharmacogenetic information in the clinical setting.AIM To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).METHODS Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2 724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.RESULTS The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h−1) was: 38.4 ×[(0.86, if days 6–10) or (0.71, if days 11–180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50]−0.4) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.CONCLUSIONS The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.

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Section: Figurementioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

151

163

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“…The total antipyrine clearance and clearance for production of metabolites observed for the population studied (Table 2) were considerably higher than those reported for different populations including patients treated with antiepileptics such as phenytoin and/or carbamazepine (22,27). It should be emphasized, however, that dexamethasone, an inducer of CYP3A4 (33,34), is able to potentially induce the formation of OHA and, consequently, to increase total antipyrine clearance. McCune et al (34) reported that dexamethasone at clinically used doses increased CYP3A4 activity with extensive intersubject variability in healthy volunteers.…”

Section: Resultsmentioning

confidence: 99%

“…It should be emphasized, however, that dexamethasone, an inducer of CYP3A4 (33,34), is able to potentially induce the formation of OHA and, consequently, to increase total antipyrine clearance. McCune et al (34) reported that dexamethasone at clinically used doses increased CYP3A4 activity with extensive intersubject variability in healthy volunteers. ASON in man are available, the results presented here suggest the involvement of the same or similar enzymes in the oxidation of antipyrine and ASOX.…”

Section: Resultsmentioning

confidence: 99%

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

Marques

Takayanagui

Lanchote

2002

Braz J Med Biol Res

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The present study investigates the isoform(s) of cytochrome P450 (CYP) involved in the metabolism of albendazole sulfoxide (ASOX) to albendazole sulfone (ASON) in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+)-ASOX, (-)-ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f) of ASON and of the (+) and (-)-ASOX enantiomers were calculated and compared to total antipyrine clearance (CL T ) and the clearance for the production of the three major antipyrine metabolites (CL m ). A correlation (P≤0.05) was obtained only between the CL T of antipyrine and the CL/f of ASON (r = 0.67). The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL T of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.

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“…The chemosensitivity of the primary tumor is the major determinant of the response to systemic treatment for brain metastases (92,95), although asymptomatic brain metastases may have lower responses than systemic tumors to systemic chemotherapy (82). Dexamethasone and enzyme-inducing anti-epileptic drugs (EIAEDs) can induce cytochrome p450 3A isoenzymes, including CYP3A4, which metabolizes chemotherapeutic agents (96,97) including paclitaxel, irinotecan, vinorelbine, cyclophosphamide, doxorubicin, etoposide, ifosfamide, teniposide, erlotinib, and gefitinib. Therefore, co-administration of EIAEDs or dexamethasone may increase the metabolism of chemotherapeutic agents, lower plasma concentrations, and reduce efficacy.…”

Section: Discussionmentioning

confidence: 99%