Biomedical subjects

Steffen Bauer

Publications and source records attributed to Steffen Bauer.

At least 19 recordsLinked to original sources

PubMed2005

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis.

BACKGROUND: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. OBJECTIVE: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. MATERIALS AND METHODS: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. RESULTS AND DISCUSSION: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF. CONCLUSION: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

Adult↗

PubMed2005

Quantification of pravastatin in human plasma and urine after solid phase extraction using high performance liquid chromatography with ultraviolet detection.

A high performance liquid chromatography (HPLC) method for the estimation of pravastatin in human plasma and urine samples has been developed. The preparation of the samples was performed by automated solid phase extraction using clonazepam as internal standard. The compounds were separated by isocratic reversed-phase HPLC (C(18)) and detected at 239 nm. The method was linear up to concentrations of 200 ng/ml in plasma and 2000 ng/ml in urine. The intra-assay variability for pravastatin in plasma ranged from 0.9% to 3.5% and from 2.5% to 5.3% in urine. The inter-assay variability ranged from 9.1% to 10.2% in plasma and from 3.9% to 7.5% in urine. The validated limits of quantification were 1.9 ng/ml for plasma and 125 ng/ml for urine estimation. These method characteristics allowed the determination of the pharmacokinetic parameters of pravastatin after administration of therapeutic doses.

Chromatography, High Pressure Liquid↗

PubMed2005

No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract.

We evaluated the pharmacokinetic interaction between a low-hyperforin St John's wort (SJW) extract and alprazolam, caffeine, tolbutamide, and digoxin. Previous reports on other SJW products had shown remarkably decreased plasma concentrations of certain co-medicated drugs, which was attributed to an inducing effect of SJW on cytochrome P-450 (CYP) and p-glycoprotein (p-gp) activity. Two randomised, placebo-controlled studies were performed with 28 healthy volunteers (age 18 - 55 years) in each study. In study A, single doses of alprazolam (1 mg; substrate of CYP3A4) and caffeine (100 mg; CYP1A2) were given on days 1 and 11. In study B, single doses of tolbutamide (500 mg, days 1 and 11; CYP2C9) and multiple doses of digoxin (0.75 mg on days -2 and -1, 0.25 mg/die on days 1 to 11; p-gp) were given. The participants received SJW (Esbericum capsules; 240 mg/die of extract, 3.5 mg hyperforin) or placebo on days 2 to 11. Blood for pharmacokinetic analysis was drawn on days 1 and 11. No statistically significant differences were found in the primary kinetic parameter, AUC0 - 24, of alprazolam, caffeine (AUC0 - 12), paraxanthine, tolbutamide, 4-hydroxytolbutamide, and digoxin between the placebo group and the SJW group at the end of the study. The SJW-induced change in AUCs was less than 12 % of the initial median AUC of the participants in studies A and B, thus clinically irrelevant. On day 11, trough concentrations were 2.0 (range 0.6 - 4.1) microg/L and 1.0 (0.2 - 3.9) microg/L for hypericin and pseudohypericin, respectively, whereas hyperforin concentrations were below the quantification limit (< 1 microg/L). Kinetics of investigated probe drugs were only marginally influenced by concomitant treatment with Esbericum capsules. This may be due in particular to the low hyperforin plasma concentration as this SJW component has been shown to activate the PXR receptor which regulates expression of CYP3A4 and p-gp. Our findings corroborate the view that reports about interactions of other SJW extracts seem not to be predictive for the product we studied.

Adult↗

PubMed2004

Impact of cytochrome P-450 inhibition by cimetidine and induction by carbamazepine on the kinetics of hypericin and pseudohypericin in healthy volunteers.

This study evaluated the influence of cimetidine and carbamazepine on the pharmacokinetics of the St. John's wort (SJW) ingredients hypericin and pseudohypericin. In a placebo-controlled, double blind study, 33 healthy volunteers were randomized into three treatment groups that received SJW extract (LI160) with different comedications (placebo, cimetidine, and carbamazepine) for 7 days after a run-in period of 11 days with SJW alone. Hypericin and pseudohypericin pharmacokinetics were measured on days 10 and 17. Between-group comparisons showed no statistically significant differences in AUC(0-24), C(max), and t(max) values for hypericin and pseudohypericin. Within-group comparisons, however, revealed a statistically significant increase in hypericin AUC(0-24) from a median of 119 (range 82-163 microg h/l) to 149 microg h/l (61-202 microg h/l) with cimetidine comedication and a decrease in pseudohypericin AUC(0-24) from a median of 51.0 (16.4-102.9 microg h/l) to 36.4 microg h/l (14.0-102.0 microg h/l) with carbamazepine comedication compared to the baseline pharmacokinetics in each group. Hypericin and pseudohypericin pharmacokinetics were only marginally influenced by comedication with the enzyme inhibitors and inducers cimetidine and carbamazepine.

Adult↗

PubMed2004

The effect of sevelamer on the pharmacokinetics of cyclosporin A and mycophenolate mofetil after renal transplantation.

BACKGROUND: After renal transplantation, patients with insufficient graft function may require phosphate binders. It is still unknown if sevelamer, a new calcium-free phosphate binder, interferes with the uptake of immunosuppressants. We studied its effects on the pharmacokinetics of cyclosporin A (CsA) and mycophenolate mofetil. METHODS: We examined 10 adults and eight children with stable renal graft function and stable CsA trough levels. A 12 h pharmacokinetic profile (10 observation points) was conducted without sevelamer, after a single dose and after 4 days of treatment with it. CsA levels were measured with both a monoclonal antibody assay (CEDIA) and a polyclonal antibody assay (FPIA), mycophenolic acid (MPA) levels by EMIT assay and CsA metabolites AM1, AM9 and AM4N by a modified HPLC method. RESULTS: Sevelamer had no significant effect on CsA kinetics [area under the curve (AUC), peak concentration (C(max)), time of C(max)]. The AUC of AM1 was decreased by 30% and C(max) by 25% after 4 days of sevelamer intake. MPA levels were significantly reduced by a mean of 25% of the AUC (P<0.05) and by 30% of the C(max) after a single dose of sevelamer. CONCLUSIONS: A single sevelamer dose reduces the C(max) and the AUC of MPA. Its intake for several days does not significantly influence CsA kinetics.

Adolescent↗

PubMed2004

Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics.

OBJECTIVE: We compared the pharmacogenetic effects of OATP-C (organic anion transporting polypeptide C) *1a, *1b (A388G), and *5 (T521C) haplotypes on single-dose pharmacokinetics of pravastatin in white subjects. METHODS: Thirty healthy white male subjects were grouped according to their OATP-C haplotype. Each group contained 10 individuals who were either homozygous or heterozygous carriers of the *1a, *1b, or *5 haplotype. After a single oral dose of 40 mg pravastatin, we analyzed kinetic parameters of pravastatin disposition. RESULTS: Values for the area under the plasma concentration-time curve from time 0 to 6 hours [AUC(0-6)] in *1a/*1a, *1a/*1b or *1b/*1b, and *1a/*5 individuals were 114.5 +/- 68.6 microg. L(-1). h, 74.8 +/- 35.6 microg. L(-1). h, and 163.0 +/- 64.6 microg. L(-1). h, respectively, with highly significant differences across all 3 study groups (P =.006) and between subjects carrying the *1b and *5 haplotype (P =.002). Strikingly, values of AUC(0-6) from the OATP-C *1b group were more than 60% lower than those derived from carriers of the wild-type OATP-C *1a haplotype, although this difference failed to reach statistical significance. However, the amount of pravastatin excreted into the urine from time 0 to 12 hours [Ae(0-12)] was significantly diminished in the OATP-C *1b haplotype group (1729 +/- 907 microg) compared with *1a wild-type control subjects (2974 +/- 1590 microg) (P =.049). CONCLUSION: There was a significant effect of tested OATP-C variant haplotypes on pravastatin disposition. Whereas *5 expression delayed the hepatocellular uptake of pravastatin, *1b expression seemed to accelerate OATP-C-dependent uptake of the drug.

Administration, Oral↗

PubMed2004

Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics.

INTRODUCTION: In the treatment of heart failure and hypertension with metoprolol, ultrarapid metabolizers (UMs) may not achieve optimal target concentrations with recommended doses. We compared metoprolol pharmacokinetics and effects in UMs with extensive metabolizers (EMs) and with poor metabolizers (PM) as an additional reference group. METHODS: After a single dose of 100 mg metoprolol, pharmacokinetics, resting and exercise heart rate, and blood pressure were analyzed in relation to the CYP2D6 genotypes. We included 12 UMs, 13 EMs, and 4 PMs (healthy volunteers). CYP2D6 genotyping covered alleles *1 to *6 , *9 , *10 , *35 , and *41 and the duplications. beta 1 -Adrenergic receptor polymorphisms Ser49Gly and Arg389Gly were included as factors possibly interfering with the pharmacokinetic-pharmacodynamic relationship of metoprolol. RESULTS: Median total metoprolol clearance values were 31, 168, and 367 L/h and median maximum plasma concentrations were 260, 118, and 67 microg/L in PMs, EMs, and UMs, respectively ( P < .0001). At 6 hours after administration, metoprolol reduced the exercise heart rate by median values of 31, 21, and 18 beats/min in PMs, EMs, and UMs, respectively ( P = .01). Blood pressure did not significantly differ according to CYP2D6 . CONCLUSIONS: A linear relationship between the number of active CYP2D6 genes and metabolic clearance of metoprolol was found and the the median clearances differed by more than 10-fold between the PM and the UM groups. Metoprolol pharmacodynamics, however, differed only by less than 2-fold, and there was only a marginal difference in metoprolol efficacy on heart rate between the EM and UM groups.

Administration, Oral↗

PubMed2004

Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction.

OBJECTIVE: Hyperforin (HYF) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St John's wort (SJW) comedication. This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine (INN, ciclosporin) (CSA). METHODS: In a crossover study, 10 renal transplant patients were randomized into 2 groups and received SJW extract (900 mg/d) containing low or high concentrations of HYF for 14 days in addition to their regular regimen of CSA. After a 27-day washout phase, patients were crossed over to the other SJW treatment for 14 days. Blood concentrations of CSA were measured by immunoassay. RESULTS: The study showed a significant difference between the effects of the 2 SJW preparations on CSA pharmacokinetics (area under the plasma concentration-time curve within one dosing interval [AUC 0-12 ], P < .0001, ANOVA). AUC 0-12 values (monoclonal) with high-HYF SJW comedication were 45% lower (95% confidence interval [CI], -37% to -54%; P < .05, Student-Newman-Keuls test) than for low-HYF SJW. The dose-corrected AUC 0-12 for CSA (monoclonal) decreased significantly compared with baseline by 52% (95% CI, -46% to -56%; P < .05) after 2 weeks of comedication with high-HYF SJW. Values of peak concentration in plasma and drug concentration at the end of one dosing interval were affected to a similar extent, with reductions by 43% (95% CI, -36% to -48%) and 55% (95% CI, -48% to -60%), respectively. In addition, a 65% (95% CI, 53% to 85%; P < .05) increase in daily CSA doses was required during high-HYF SJW treatment. In contrast, coadministration of low-HYF SJW did not significantly affect CSA pharmacokinetics and did not require CSA dose adjustments compared with baseline. CONCLUSION: HYF content of SJW extracts significantly affects the extent of the pharmacokinetic interaction between CSA and SJW.

Adult↗

PubMed2004

MCG to ECG source differences: measurements and a two-dimensional computer model study.

In this work we combine body surface potential map (BSPM) and magnetocardiogram (MCG) measurements with computer simulations in order to elucidate a recent thesis that claims the orthogonality of the main sources of MCG and ECG. Body surface currents and MCG pseudo currents are calculated from measured BSPM and MCG data, respectively. In contrast to the MCG-ECG source orthogonality thesis, we observe the main orientation of the BSPM currents and MCG pseudo currents to have similar axis during most of the depolarization R wave. In an attempt to explain such measurements we simulate a 2D transmural slice of the left ventricle in contact to a volume conductor. The main magnetic source currents along the wave front are indeed orthogonal to the extracellular electric current. However, fiber orientation inhomogeneity through the ventricular wall, volume conductor interface, wave front shape and extra- and intracellular potential distributions, all distort the symmetry of the current loops that contain the wave front currents. The resulting asymmetry rotates the main axis of the pseudo MCG currents away from the orthogonal axis of the body surface currents. Thus, the simulation results could solve the apparent contradiction between the orthogonal source theory and the observed similar ECG and MCG main current axis.

Body Surface Potential Mapping↗

PubMed2004

Parallel multigrid preconditioner for the cardiac bidomain model.

The bidomain equations are widely used for the simulation of electrical activity in cardiac tissue but are computationally expensive, limiting the size of the problem which can be modeled. The purpose of this study is to determine more efficient ways to solve the elliptic portion of the bidomain equations, the most computationally expensive part of the computation. Specifically, we assessed the performance of a parallel multigrid (MG) preconditioner for a conjugate gradient solver. We employed an operator splitting technique, dividing the computation in a parabolic equation, an elliptical equation, and a nonlinear system of ordinary differential equations at each time step. The elliptic equation was solved by the preconditioned conjugate gradient method, and the traditional block incomplete LU parallel preconditioner (ILU) was compared to MG. Execution time was minimized for each preconditioner by adjusting the fill-in factor for ILU, and by choosing the optimal number of levels for MG. The parallel implementation was based on the PETSc library and we report results for up to 16 nodes on a distributed cluster, for two and three dimensional simulations. A direct solver was also available to compare results for single processor runs. MG was found to solve the system in one third of the time required by ILU but required about 40% more memory. Thus, MG offered an attractive tradeoff between memory usage and speed, since its performance lay between those of the classic iterative methods (slow and low memory consumption) and direct methods (fast and high memory consumption). Results suggest the MG preconditioner is well suited for quickly and accurately solving the bidomain equations.

Algorithms↗

PubMed2004

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients.

AIM: This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. METHODS: Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. RESULTS: No significant differences were observed between groups. Differences in mean tacrolimus C(0) values between carriers and noncarriers of each haplotype ranged from -0.04 microg/litre (95% confidence interval: -0.53 to 0.60) to -23 microg/litre (-1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. CONCLUSION: MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.

Adolescent↗

PubMed2004

Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers.

BACKGROUND: The oral hypoglycaemic drug nateglinide is eliminated from the human body via hepatic biotransformation and renal tubular secretion. According to in vitro data, about 70% of nateglinide intrinsic clearance may be mediated by cytochrome P450 (CYP) 2C9 and a smaller fraction by CYP3A4 and CYP2D6. OBJECTIVE: To assess the impact of CYP2C9 polymorphisms and of the CYP2D6 poor metaboliser genotype on the pharmacokinetics of nateglinide and its effects on insulin, glucose and glucagon in plasma. DESIGN AND PARTICIPANTS: A prospective clinical study in 26 healthy volunteers chosen for their CYP2C9 and CYP2D6 genotype was conducted with individuals carrying wild-type genotype as reference group. METHODS: Serial plasma nateglinide, glucose, insulin and glucagon concentrations were measured over 34 hours after a 180 mg dose of nateglinide under challenge with 75 g of oral glucose at 0, 4 and 8 hours after nateglinide intake. Kinetics were evaluated by nonparametric methods and by population pharmacokinetic-pharmacodynamic modelling. RESULTS: Significantly reduced oral nateglinide clearance was found in carriers of CYP2C9*3 alleles, (p < 0.01), whereas carriers of CYP2C9*2 alleles had kinetic parameters similar to those of carriers of the wild-type allele (p = nonsignificant). Median total clearances were 7.9, 8.4, 6.5, 6.9, 5.8 and 4.1 L/h in carriers of the CYP2C9 genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3. Median clearance in three carriers of two deficient CYP2D6 alleles was 9.4 L/h. These differences in nateglinide kinetics due to CYP2C9 genotypes did not result in statistically significant differences in plasma glucose, insulin and glucagon. Pharmacokinetic-pharmacodynamic modelling revealed a minor effect of CYP2C9 genotype on insulin and glucose, and extrapolations indicated that carriers of the CYP2C9*3/*3 genotype may be at a slightly higher risk of hypoglycaemia compared with carriers of CYP2C9*1, particularly when taking nateglinide doses above 120 mg. CONCLUSION: The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients.

Adult↗

PubMed2003

Rapid and simple method for the analysis of nateglinide in human plasma using HPLC analysis with UV detection.

Nateglinide (NA) is a novel oral mealtime glucose regulator, recently approved for the treatment of type II diabetes mellitus. To facilitate clinical studies investigating the dependence of NA elimination on the genotype of cytochrome P450 isoenzymes, we developed a rapid HPLC method for determination of NA in human plasma samples. The validated limit of quantitation (LOQ) of 0.1 microg/ml is low enough to allow determination of pharmacokinetic parameters of the substance. The intra-assay coefficients of variation (CV) ranged from 1.6 to 12.9% at NA concentrations of 0.5-7.5 microg/ml. The inter-assay variation for the same plasma concentrations ranged from 3.8 to 8.4%. The calibration was linear in the range of 0.1-20 microg/ml. For the quantitation of NA, only 50 microl of plasma were needed. Following protein precipitation in human plasma, the samples were separated by isocratic reversed phase HLPC and analyzed using ultraviolet detection at 210 nm. Sample preparation time and analysis time are both short and allow rapid analysis of large sample sets.

Anticonvulsants↗

PubMed2003

Simultaneous determination of celecoxib, hydroxycelecoxib, and carboxycelecoxib in human plasma using gradient reversed-phase liquid chromatography with ultraviolet absorbance detection.

A new HPLC method for the simultaneous determination of celecoxib, carboxycelecoxib and hydroxycelecoxib in human plasma samples has been developed. Following a solid-phase extraction procedure, the samples were separated by gradient reversed-phase HLPC (C(18)) and quantified using UV detection at 254 nm. The method was linear over the concentration range 10-500 ng/ml. The intra-assay variability for the three analytes ranged from 4.0 to 12.6% and the inter-assay variability from 4.9 to 14.2%. The achieved limits of quantitation (LOQ) of 10 ng/ml for each analyte allowed the determination of the pharmacokinetic parameters of the analytes after administration of 100 mg celecoxib.

Celecoxib↗

PubMed2003

Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers.

INTRODUCTION: In vitro data indicate that biotransformation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor fluvastatin is catalyzed by the cytochrome P450 (CYP) enzyme 2C9. The consequences of CYP2C9 genetic polymorphisms on fluvastatin pharmacokinetics and on its efficacy have not been investigated in humans thus far. METHODS: Twenty-four healthy heterozygous or homozygous carriers of the CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3) and 2 individuals with the deficient CYP2D6 genotype *4/*4 took 40 mg racemic fluvastatin daily for 14 days. All subjects had also been genotyped for CYP2C8, CYP2C19, and CYP2D6 polymorphisms. Pharmacokinetics was analyzed after the first fluvastatin administration. Serum lipid concentrations were measured before fluvastatin intake and on day 15. Plasma concentrations of (+)-3R,5S-fluvastatin and of (-)-3S,5R-fluvastatin were quantified by enantiospecific HPLC. RESULTS: Pharmacokinetics of both enantiomers showed statistically significant differences according to the number of CYP2C9*3 alleles (P <.0001, F test). Mean (and SD) values for area under the curve of the active (+)-3R,5S-fluvastatin in carriers of the genotype CYP2C9*1/*1, *1/*3, and *3/*3 were 173 (85) micro g. L(-1). h, 231 (85) micro g. L(-1). h, and 533 (120) micro g. L(-1). h, respectively. The corresponding values for area under the curve of (-)-3S,5R-fluvastatin were 227 (133) micro g. L(-1). h, 360 (103) micro g. L(-1). h, and 1126 (311) micro g. L(-1). h for CYP2C9*1/*1, *1/*3, and *3/*3, respectively. The CYP2C9*2 variant did not have any significant influence on fluvastatin kinetics, nor did the CYP2C8*3 allele, which was tightly linked with CYP2C9*2. Total serum cholesterol and low-density lipoprotein cholesterol concentrations decreased significantly during the 14-day treatment period (P <.001), but no correlation with the CYP2C9 genotype was found. CONCLUSIONS: The pharmacokinetics of both enantiomers of fluvastatin depended on the CYP2C9 genotype, with a 3-fold group mean difference in the active enantiomer and even greater differences in the inactive enantiomer, but differences in plasma concentrations were not reflected in cholesterol lowering after 14 days of fluvastatin intake in healthy volunteers.

Adult↗

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↗