Biomedical subjects

Steffen Bauer

Publications and source records attributed to Steffen Bauer.

28 records · Page 2Linked to original sources

PubMed2003

Cytochrome p450 3A4 messenger ribonucleic acid induction by rifampin in human peripheral blood mononuclear cells: correlation with alprazolam pharmacokinetics.

OBJECTIVE: There is significant interest in the assessment of the individual cytochrome p450 (CYP) 3A4 activity. We analyzed whether CYP3A4 messenger ribonucleic acid (mRNA) concentrations in leukocytes reflect CYP3A activity in the liver measured by alprazolam as an in vivo probe drug. We also wanted to identify whether genetically determined high CYP3A5 expression is associated with increased alprazolam clearance. METHODS: Alprazolam plasma concentrations were measured 10 hours after intake of 1 mg alprazolam. CYP3A4 mRNA concentrations in peripheral blood mononuclear cells were quantified in 96 healthy volunteers before and after 5-day treatment with 450 mg rifampin (INN, rifampicin) daily. Genetic polymorphisms in CYP2C19, CYP3A4, and CYP3A5 were analyzed by polymerase chain reaction, restriction fragment length polymorphism, and sequencing. RESULTS: The median alprazolam concentration measured 10 hours after dosage was 8.1 mug/L (range, 4.5-14.6 mug/L) before and 1.7 mug/L (range, 0.3-4.1 mug/L) after rifampin treatment. Leukocyte CYP3A4 mRNA was detectable in all samples with a median of 28 molecules per 1 ng total ribonucleic acid before (range, 10-128 molecules per 1 ng total ribonucleic acid) and 50 molecules per 1 ng total ribonucleic acid after (range, 9-484 molecules per 1 ng total ribonucleic acid) rifampin treatment (P <.001). However, mRNA concentrations before and during rifampin induction were largely overlapping, and there was a poor correlation between mRNA concentrations and alprazolam 10-hour trough concentrations reflecting CYP3A4 activity (r = -0.4, P <.001). Alprazolam kinetics did not differ between genetically determined expressers of CYP3A5 (genotype CYP3A5*1/*3) compared with homozygous carriers of the splice site variant. A marginally significant dependence of alprazolam concentrations from the CYP2C19 allele *2 was found (P =.04). CONCLUSIONS: CYP3A4 mRNA concentrations in blood cells were very low and did not reflect systemic drug clearance mediated by CYP3A enzymes. The CYP3A5 genetic polymorphism does not appear relevant for alprazolam kinetics.

Adult↗

PubMed2003

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients.

AIM: This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). METHODS: In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. RESULTS: After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. CONCLUSION: Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.

Adult↗

PubMed2003

Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients.

BACKGROUND: This study investigated the effect of St John's wort (SJW) extract on the pharmacokinetics of the immunosuppressants tacrolimus (TAC) and mycophenolic acid (MPA). METHODS: Ten stable renal transplant patients received 600 mg SJW extract for 14 days in addition to their regular regimen of TAC and mycophenolate mofetil. RESULTS: Dose-corrected AUC((0-12)) of TAC decreased significantly from 180 ng/ml/h at baseline to 75.9 ng/ml/h after 2 weeks of SJW treatment. To maintain therapeutic TAC concentrations, dose adjustments from a median 4.5 mg/day at baseline to 8.0 mg/day under SJW treatment were required. Two weeks after discontinuation of SJW, TAC doses were reduced to a median of 6.5 mg/day. MPA pharmacokinetics remained unaffected by comedication with hypericum extract. CONCLUSIONS: Administration of SJW extract to patients receiving TAC treatment can result in a serious drug interaction leading to markedly reduced TAC blood concentrations associated with the risk of organ rejection.

Adult↗

PubMed2002

Differential effects of Saint John's Wort (hypericum perforatum) on the urinary excretion of D-glucaric acid and 6beta-hydroxycortisol in healthy volunteers.

OBJECTIVE: We investigated the effects of treatment with Saint John's wort (hypericum perforatum) extract on the urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol in order to assess the effect of this extract on the activity of hepatic xenobiotic metabolizing enzymes. METHODS: Forty-eight healthy volunteers (25 male and 23 female) received a daily dose of 1800 mg hypericum extract for 14 days. Urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol was measured in 24-h urine samples on the day preceding the initiation of hypericum treatment and after 14 days of treatment. D-Glucaric acid was measured enzymatically. Cortisol and 6beta-hydroxycortisol were quantified using high-performance liquid chromatography with ultraviolet detection. RESULTS: Urinary excretion of D-glucaric acid was unaffected after a 14-day treatment with Saint John's wort extract (26.7 micromol/day vs 27.7 micromol/day; 95% confidence interval of the difference: -1.9 to 3.8). The urinary excretion of 6beta-hydroxycortisol increased from a mean baseline value of 254 microg/day to 369 microg/day (P<0.0001) indicating induction of CYP3A. While the excretion of free cortisol was unaltered, the ratio of 6beta-hydroxycortisol to free cortisol changed significantly from 9.9 at baseline to 14.3 (95% confidence interval of the difference: 2.3-6.5) after Saint John's wort treatment. CONCLUSIONS: High-dose treatment with Saint John's wort extract induced CYP3A activity in healthy volunteers as evidenced by increased 6beta-hydroxycortisol excretion. This enzyme induction most likely contributes to the decreased bioavailability observed upon co-administration of various drugs with Saint John's wort extract. The D-glucuronic acid pathway appeared unaffected by Saint John's wort.

Adult↗

PubMed2002

Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.

PURPOSE: The use of serotonin 5-hydroxytryptamine type 3 receptor antagonists has substantially reduced, but not eliminated, nausea and vomiting in cancer chemotherapy. This study sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on cytochrome P-450 2D6 (CYP2D6) genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated. PATIENTS AND METHODS: Included in the study were 270 cancer patients receiving their first day of chemotherapy. Nausea and vomiting were documented using standardized interviews. The intensity of nausea was measured with visual analog scales before and twice during the chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 hours after drug administration was analyzed in a subgroup of 42 patients. CYP2D6 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients (P <.03). Approximately 30% of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined ultrarapid meta-bolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 hours (P <.001) and within the period 5 to 24 hours (P <.03) after treatment than all the other patients; the tendency for nausea was similar. This difference was more pronounced in patients treated with tropisetron than in those treated with ondansetron. CONCLUSION: Antiemetic treatment with tropisetron or ondansetron could be improved by adjustment for the CYP2D6 genotype; approximately 50 subjects would have to be genotyped to protect one patient from severe emesis.

Adolescent↗

PubMed2002

Simultaneous determination of ondansetron and tropisetron in human plasma using HPLC with UV detection.

A rapid and sensitive HPLC method for the simultaneous quantitation of ondansetron and tropisetron, two serotonin (5-HT) receptor antagonists frequently used in treatment and prevention of nausea and emesis, is described. The procedure involves liquid-liquid extraction of human plasma with dichloromethane coupled with reversed-phase HPLC and UV detection. The lower limits of quantification (LOQ) were 0.62 ng/mL for ondansetron and 1.25 ng/mL or tropisetron. Intra- and inter-assay coefficients of variation ranged from 1.5 to 7.5% and 5.3 to 13.7%, respectively. The sensitivity and precision were sufficient for determination of plasma concentrations after therapeutic administration of both drugs and the method can be used for the estimation of pharmacokinetic parameters.

Chromatography, High Pressure Liquid↗

PubMed2002

Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers.

BACKGROUND: Glyburide (INN, glibenclamide) is a second-generation sulfonylurea antidiabetic agent with high potency. We hypothesized that glyburide may be a substrate of cytochrome P450 2C9 (CYP2C9), an enzyme that has two low-activity amino acid variants-Arg144Cys (CYP2C9*2) and Ile359Leu (CYP2C9*3). We explored the impact of these polymorphisms on glyburide pharmacokinetics and the effects on insulin and glucose concentrations. METHODS: Twenty-one healthy volunteers who represented all possible combinations of the two variant alleles were studied (genotypes CYP2C9*1/*1, *1/*2, *2/*2, *1/*3, *2/*3, and *3/*3 ). They received a single oral dose of 3.5 mg glyburide followed by 75 g glucose at 1, 4.5, and 8 hours after administration of glyburide. Glyburide was quantified in plasma by reversed-phase HPLC. Venous blood concentrations of glyburide, insulin, and glucose were analyzed with a population pharmacokinetic-pharmacodynamic model by use of NONMEM statistical software. RESULTS: Pharmacokinetics of glyburide depended significantly on CYP2C9 genotypes. In homozygous carriers of the genotype *3/*3, total oral clearance was less than half of that of the wild-type genotype *1/*1 (P <.001). Correspondingly, insulin secretion measured within 12 hours after glyburide ingestion was higher in carriers of the genotype *3/*3 compared with the other genotypes (P =.028), whereas the differences in glucose concentrations were not significant. CONCLUSIONS: Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.

Adult↗

PubMed2002

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction.

OBJECTIVE: The correct in vivo quantification of aryl hydrocarbon receptor-mediated induction of cytochrome P450 1A2 (CYP1A2) in humans is a long-standing question. We compared the performance of several modifications of the caffeine test for measurement of CYP1A2 activity in subjects with exceptionally high, low, or absent enzyme induction. METHODS: CYP1A2 activity was measured in 2 women highly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in 1 man moderately exposed, and in 50 control subjects (30 nonsmokers and 20 heavy smokers). After the application of a test dose, caffeine demethylation was detected with the carbon 13 breath test, the total clearance, and several serum and urinary metabolite ratios. RESULTS: In the highly TCDD-exposed persons, results of the breath test (cumulative 15-minute dose), the total caffeine clearance, the serum metabolic ratio paraxanthine/caffeine (30 and 120 minutes after application), and the urinary metabolic ratio sum of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methyluric acid (1U), and 1-methylxanthine (1X) over 1,7-dimethyluric acid (17U) showed a CYP1A2 activity 8 to 10 times higher than the mean of nonsmokers. In contrast, two caffeine urinary metabolic ratios with the parent substance in the denominator did not reflect the CYP1A2 enzyme induction. These ratios strongly depended on urine flow. For the breath test, only results evaluated for a short sampling period (eg, 15 minutes after application) revealed the high induction. Compared with nonsmokers, higher mean values (maximally 1.8 times) were observed in smokers with all tests. CONCLUSION: After high TCDD exposure, hepatic CYP1A2 activity is inducible at least 10 times in humans. Moderate TCDD exposure (up to 1000 ppt in blood fat) does not cause a CYP1A2 induction that can be measured to differentiate from background exposure individually. Therefore direct quantification of such toxins is more specific and sensitive.

Adult↗

PubMed2002

Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum ).

Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with hypericum extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of hypericum extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of hypericum extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with hypericum extract. Furthermore, comparisons were made for single-dose kinetics of hypericum-extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.

Adult↗

PubMed2002

Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers.

Tolbutamide is known to be metabolized by cytochrome P450 2C9 (CYP2C9), and the effects of the CYP2C9 amino acid polymorphisms *2 (Arg144Cys) and *3 (Ile359Leu) could be important for drug treatment with tolbutamide and for use of tolbutamide as a CYP2C9 test drug. Tolbutamide pharmacokinetics and plasma insulin and glucose concentrations were studied in 23 healthy volunteers with all six combinations of the CYP2C9 alleles *1, *2 and *3, including two subjects with the combined CYP2C9*1/*1 and CYP2C19*2/*2 genotype. Volunteers received a single oral dose of 500 mg tolbutamide, followed by 75 g oral glucose at 1, 4.5 and 8 h after tolbutamide administration. Pharmacokinetic analysis was performed using a computer program for regression analysis of nonlinear mixed effects models. The mean oral clearances of tolbutamide were 0.97 (95% confidence interval [CI] 0.89-1.05), 0.86 (95% CI 0.79-0.93), 0.75 (95% CI 0.69-0.81), 0.56 (95% CI 0.51-0.61), 0.45 (95% CI 0.41-0.49) and 0.15 (95% CI 0.14-0.16) l/h in carriers of CYP2C9 genotypes 1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3, respectively. Tolbutamide pharmacokinetics in carriers of the functionally deficient CYP2C19*2/*2 genotype were not different from those in the CYP2C19 highly active genotype. Elimination in the six CYP2C9 genotype groups could be expressed as the linear combination of three constants (0.05, 0.04, 0.01 h(-1), which were specific to the respective CYP2C9 alleles *1, *2 and *3, thus indicating a co-dominant mode of inheritance. Insulin and glucose concentration-time curves did not change with differing CYP2C9 genotypes. Tolbutamide was confirmed as a substrate of the genetically polymorphic enzyme CYP2C9. The pronounced differences in pharmacokinetics due to the amino acid variants did not significantly affect plasma insulin and glucose concentrations in healthy volunteers.

Adult↗