Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man.

Watkins, Paul B.; Wrighton, Steven; Schuetz, Erin G.; Molowa, David T.; Guzelian, Philip S.

doi:10.1172/jci113156

Cited by 433 publications

(233 citation statements)

References 35 publications

Supporting

Mentioning

223

Contrasting

Order By: Relevance

“…Nonetheless, excluding these 3 patients from the data set did not affect our findings. Glucocorticoids are known to induce CYP2C19 and CYP3A (34,35), but overall, there was no significant difference in exposure to oral glucocorticoids between genotype subsets, since similar dosing schedules were used. Thirty-seven patients (60%) received pulse methylprednisolone together with pulse cyclophosphamide.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis

Takada¹,

Arefayene²,

Desta³

et al. 2004

Arthritis & Rheumatism

149

107

View full text Add to dashboard Cite

Objective. Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes. We conducted a retrospective cohort study to test whether genetic polymorphisms of these enzymes are associated with the toxicity of, and clinical response to, cyclophosphamide in patients with lupus nephritis.Methods. Sixty-two patients with proliferative lupus nephritis treated with cyclophosphamide were genotyped for common variant alleles of CYP2B6, 2C19, 2C9, and 3A5. We examined the association between these genotypes and the following clinical end points: development of premature ovarian failure, end-stage renal disease (ESRD), doubling of serum creatinine level, and achievement of complete renal response.Results. The observed frequencies of the variant alleles CYP2B6*5, CYP2C19*2, CYP2C9*2, and CYP3A5*3 were 12.1%, 25.0%, 4.0%, and 75.8%, respectively. Patients who were either heterozygous or homozygous for CYP2C19*2 had a significantly lower risk of developing premature ovarian failure (relative risk 0.10; 95% confidence interval 0.02-0.52), after adjustment for age and total number of cyclophosphamide pulses received. In a survival analysis, patients homozygous for CYP2B6*5 (n ‫؍‬ 3) or CYP2C19*2 (n ‫؍‬ 4) had a higher probability of reaching ESRD (P ‫؍‬ 0.0005) and of doubling the creatinine level (P ‫؍‬ 0.0005) as well as a trend toward a lower probability of achieving a complete renal response (P ‫؍‬ 0.051).Conclusion. Determination of selected cytochrome P450 enzyme genotypes may be valuable for predicting the risk of premature ovarian failure in lupus nephritis patients treated with cyclophosphamide. The association of these genotypes with renal response needs further validation.Clinical trials have shown that cyclophosphamide is effective in achieving renal remission and preserving renal function in lupus nephritis (1-4). However, even with a long course (30 months or longer) of pulse cyclophosphamide therapy, up to 40% of patients fail to achieve renal remission, and up to 20% of patients develop end-stage renal disease (ESRD) (5-7).The most common long-term adverse effect of pulse cyclophosphamide is premature ovarian failure, which is of particular concern since the majority of patients with lupus nephritis are women of reproductive age. The rate of premature ovarian failure in a recently published long-term followup study of patients treated with cyclophosphamide in a controlled trial was as high as 60% (8). Several studies in lupus patients showed that the risk of this complication was dependent on the age of the patient at the initiation of therapy and the cumulaSupported in part by a clinical pharmacology training grant

show abstract

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis

Takada¹,

Arefayene²,

Desta³

et al. 2004

Arthritis & Rheumatism

149

107

View full text Add to dashboard Cite

show abstract

“…On the other hand, CYP3A accounts for about 30 and 70% of total CYP activity in the liver and small intestine, respectively [12][13][14], and intestinal first-pass metabolism mediated by CYP3A has been shown to be clinically relevant for several drugs, including cyclosporin A [15,16]. However, it remains to be fully clarified whether P-gp and/or CYP3A controls the oral bioavailability of cyclosporin A by limiting absorption from the small intestine.…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

Jin

Shimada

Yokogawa

et al. 2006

Biochemical Pharmacology

View full text Add to dashboard Cite

“…Since glucocorticosteroids induce CYP3A4, the concentration of fentanyl may decrease during their simultaneous use [86].…”

Section: Fentanylmentioning

confidence: 99%

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

Łój¹,

Olender²,

Ślęzak³

et al. 2014

Anaesthesiol Intensive Ther

View full text Add to dashboard Cite

Background: Drug-drug interactions constitute a serious health hazard in everyday clinical practice in critically ill patients. Drug-drug interactions may be pharmacokinetic or pharmacodynamic in their nature. We aimed to investigate the quantity and quality of possible drug-drug interactions, and their possible side effects in intensive care unit patients in a 12-month period. Methods: This retrospective study covered data on pharmacological treatment of 43 consecutive patients (11 females, 32 males) aged 62 ± 15 years, hospitalized between January 2015 and February 2016. Pharmacokinetic DDIs were identified and graded. Only severe and clinically important drug-drug interactions were subjected for further analysis. Results: Median baseline SAPS III was 53 (IQR 38-67) points. Median intensive care unit stay was 12 (6-25) days. Subjects were treated with a median number of 22 (12-27) drugs. We identified 27 (16-41) possible drug-drug interactions per patient, including 3 (1-7) drug-drug interactions of a severe grade. The total number of severe and clinically important drug-drug interactions was 253 of which 227 were analyzed in detail. No possible side-effects of drug-drug interactions were identified. Conclusions: DDIs as well as their side-effects are challenging regarding their precise evaluation, especially due to the need for multidrug treatment in critically ill patients. Concentration-controlled therapy should be recommended, especially for treatment with vancomycin, digoxin and valproate. Pantoprazole should be a proton pump-inhibitor of choice. Drug dose modification is necessary in combined treatment with fluconazole and amiodarone or rifampicin. From a clinical point of view, the most important impact of drug-drug interactions is on antibiotic treatment effectiveness, especially with meropenem when valproate is also prescribed.

show abstract

Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man.

Cited by 433 publications

References 35 publications

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

Farmakokinetyczne interakcje międzylekowe w oddziale intensywnej terapii – obserwacje jednoośrodkowe i przegląd piśmiennictwa

Contact Info

Product

Resources

About