Microsomal Enzyme Induction and Clinical Aggravation of Porphyria: The Evaluation of Human Urinary 6β‐Hydroxycortisol/Cortisol Ratio as the Index of Hepatic CYP3A4 Activity

Uejima, Etsuko; Takahashi, Kyoko; Morisaki, Tomoko; Ohno, Munekazu; Nishida, Yoko; Moriya, M.; Kaido, Misako; Abe, Kazuo; Sakoda, Saburo; Yanagihara, Takehiko; Kurokawa, Nobuo; Azuma, Junichi

doi:10.1177/0091270002042012012

Cited by 7 publications

(3 citation statements)

References 24 publications

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“…Furthermore, induction of CYP3A4 by luseogliflozin was observed at a concentration of 10 μmol/L in vitro. However, the 6β-hydroxycortisol/cortisol ratio, a marker for CYP3A4 induction [ 16 ], did not increase after 7 days of multiple doses of up to 25 mg of luseogliflozin in patients with T2DM in a clinical study conducted in the United States of America (Taisho Pharmaceutical Co., Ltd., data on file). Therefore, luseogliflozin is unlikely to induce CYP3A4 in clinical use.…”

Section: Discussionmentioning

confidence: 99%

Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

et al. 2015

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IntroductionWe investigated the possibilities of drug–drug interactions between luseogliflozin, a sodium–glucose co-transporter-2 inhibitor, and oral antidiabetic drugs (OADs) in healthy Japanese males.MethodsWe conducted six independent studies to investigate potential drug–drug interactions between 5 mg luseogliflozin and the following OADs usually used in Japan: 1 mg glimepiride, 250 mg metformin, 30 mg pioglitazone, 50 mg sitagliptin, 50 mg miglitol, or 0.6 mg voglibose (0.2 mg before each meal). Twelve subjects were enrolled in each study. The glimepiride, metformin, sitagliptin, and miglitol studies were randomized, open-label, single-dose, three-way crossover studies. The pioglitazone and voglibose studies were open-label studies, where a single dose of luseogliflozin was added to multiple doses of pioglitazone or voglibose. The endpoints were the area under the curve from 0 to 24 h (AUC0–24h) or to infinity (AUCinf) and the maximum concentration (Cmax) of each drug administered alone or in combination.ResultsThe 90% confidence intervals (CIs) of the geometric mean ratio (GMR) for Cmax of luseogliflozin in the pioglitazone and miglitol studies were beyond the reference range for bioequivalence (0.80–1.25) (miglitol: 0.851 [0.761, 0.952]; pioglitazone: 1.16 [1.04, 1.30]). However, the 90% CIs for AUC0–24h were within the reference range. The 90% CIs of the GMRs for Cmax and AUC0–24h of pioglitazone were beyond the reference range (Cmax 0.884 [0.746, 1.05]; AUC0–24h 0.896 [0.774, 1.04]), but the 90% CIs for the active metabolites of pioglitazone were within the reference range. For the other combinations tested, the 90% CIs and GMRs for luseogliflozin and the individual OADs were within the reference range.ConclusionNo clinically meaningful interactions were observed between luseogliflozin and six commonly used OADs in Japan, although there were some changes in the pharmacokinetics of pioglitazone co-administered with luseogliflozin and for luseogliflozin co-administered with miglitol or pioglitazone.FundingTaisho Pharmaceutical Co., Ltd.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0209-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

et al. 2015

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“…Furthermore, in different reported cases of porphyrias associated with the administration of epileptic drugs, significant increases were found in the urinary excretion of porphyrins, accompanied by a high degree of liver enzyme induction, evaluated using the aminopyrine breath test (3) and the urinary excretion of 6β-hydroxycortisol (4). In non-porphyric subjects treated in monotherapy with carbamazepine, McGuire et al (6) found a significant increase in the urinary excretion of porphyrins and 6β-hydroxycortisol.…”

Section: Introductionmentioning

confidence: 99%

Effect of Antiepileptic Drugs on the Urinary Excretion of Porphyrins in Non-porphyric Subjects

Tutor-Crespo¹,

Hermida²,

Tutor³

2005

J Pharmacol Sci

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Abstract. The action of some anticonvulsant drugs as the causal agents of attacks of acute porphyria has been widely documented in the literature. However, little attention has been paid to the effect of these drugs on the urinary excretion of porphyrins in non-porphyric subjects. In a sample of 82 epileptic patients treated with phenobarbital (n = 54), phenytoin (n = 64), carbamazepine (n = 33), and valproate (n = 8), the daily doses were expressed according to a drug score that would reflect the capacity of these drugs as enzymatic inducers when administered in polytherapy. A significantly increased urinary excretion of D-glucaric acid (DGA) and porphyrins was found in this group of patients (P<0.001), with coproporphyrin being the major fraction in all cases (>60%). Urinary DGA had a highly significant correlation with the drug score (r = 0.783, P<0.001); however, no significant correlations were found between the urinary porphyrins and DGA (r = 0.005) or the drug score (r = 0.053). Neither was any significant relationship found between the urinary porphyrins and the serum activity of 5'-nucleotidase (r = 0.066) or the presence of a cholestasis objectivized through the presence of the isoform of γ-glutamyltransferase with β-globulins electrophoretic mobility. However, in a group of 10 patients a significant correlation was found between the urinary excretion of porphyrins and β-N-acetylhexosaminidase (r = 0.790, P<0.01). Therefore, it does not appear that the liver enzyme induction, or even a subclinical cholestasis, produced by the antiepileptic drugs administered to these patients may serve to explain the increase in the urinary excretion of porphyrins. A possible renal origin is proposed for the increase of urinary porphyrins in these cases.

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“…Estimation of urinary ratio of 6 β-hydroxycortisol/cortisol (6 β-OHC/C) has been suggested as a simple non-invasive biochemical marker to determine the activity of CYP3A4 in human (Wilkinson, 1996;Galteau and Shamsa, 2003). Although the ratio does not always correlate with the disposition of CYP3A substrate drugs, including the typical phenotyping probe drugs such as [ 14 C]-erythromycin and midazolam (Hunt et al 1992;Watkins et al 1992;Kinirons et al 1993Kinirons et al , 1999, but recent studies have described successful utilization of the urinary ratio 6 β-OHC/C as a measure of CYP3A induction (Saima et al 2002;Uejima et al 2002;ELDesoky et al 2005;Yeo et al 2006). Furthermore, the urinary ratio has also been studied in some disease conditions to elucidate a possible correlation of CYP3A activity with disease states such as hepatic disease, thyroid disorders and cancer (NG et al 1996;Zheng et al 2001;Szucs et al 2003;Kishino et al 2004;Hoshiro et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Study of the Urinary Ratio of 6 β-Hydroxycortisol/Cortisol as a Biomarker of CYP3A4 Activity in Egyptian Patients with Chronic Liver Diseases

et al. 2006

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SummaryThe urinary ratio of 6 β-hydroxycortisol/cortisol (6 β-OHC/C) as a biomarker of CYP3A4 metabolizing activity has been studied in Egyptian patients with chronic liver cirrhosis associated with previous hepatic Schistosomiasis infection to determine any possible alteration in enzyme activity. The ratio of 6-β OHC/C was determined in morning urine samples collected from 8:00 a.m. to 12:00 p.m. in healthy adults (n = 36) and patients with liver cirrhosis (n = 57). The median age for control was 27 years (range: 18–50 years) and 50 years (range: 27–75 years) for patients. 6 β-OHC was detected in urine by ELIZA kits (Stabiligen, France). Patients with liver cirrhosis were categorized according to Child Pugh Classification into Child B (n = 28) and Child C (n = 29) classes. Cholestasis was observed in 9/28 of Child B class and 8/29 of Child C class of patients. The control subjects showed gender-related difference in the urinary ratio of 6 β-OHC/C. A significant reduction (P < 0.001) in 6 β-OHC/C ratio was observed only in Child C patients in comparison with control subjects. Regression analysis showed a significant correlation (P < 0.05) between 6 β-OHC/C ratio and serum albumin. The influence of cholestasis on the urinary ratio of 6-β OHC/C was observed on cirrhotic patients of Child B class. In conclusion, patients with chronic liver cirrhosis might have a reduction of metabolizing activity of CYP3A4 enzymes which could be identified by measuring the urinary ratio of 6 β-OHC/C. This reduction is more apparent in severe liver injury (Child C class). Therefore, it is important to understand the metabolic fate of drugs metabolized by 3A4 enzymes in patients with liver cirrhosis to avoid drug accumulation that might lead to development of drug toxicity.

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Microsomal Enzyme Induction and Clinical Aggravation of Porphyria: The Evaluation of Human Urinary 6β‐Hydroxycortisol/Cortisol Ratio as the Index of Hepatic CYP3A4 Activity

Cited by 7 publications

References 24 publications

Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

Absence of Drug–Drug Interactions Between Luseogliflozin, a Sodium–Glucose Co-transporter-2 Inhibitor, and Various Oral Antidiabetic Drugs in Healthy Japanese Males

Effect of Antiepileptic Drugs on the Urinary Excretion of Porphyrins in Non-porphyric Subjects

Study of the Urinary Ratio of 6 β-Hydroxycortisol/Cortisol as a Biomarker of CYP3A4 Activity in Egyptian Patients with Chronic Liver Diseases

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