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Biomedical subjects

U Fuhr

Publications and source records attributed to U Fuhr.

At least 55 records · Page 3Linked to original sources
PubMed1996

Investigation of nifedipine absorption in different regions of the human gastrointestinal (GI) tract after simultaneous administration of 13C- and 12C-nifedipine.

OBJECTIVE: To evaluate the absorption of nifedipine in man from four different sites of the gastrointestinal tract. METHODS: On separate occasions, nifedipine solution was administered locally to the stomach, the small intestine and two sites in the colon in 4 healthy male volunteers (age 29-34 y weight 73-82 kg, non-smokers) using a remote controlled drug delivery device (HF-capsule). In order to assess absolute and relative bioavailabilities, an intravenous infusion was given on a separate occasion and all treatments were accompanied by a simultaneous oral dose of a stable-isotope labelled nifedipine solution. This allowed to minimise the influence of intra-individual variability. Plasma samples were collected up to 24 h post dose and faeces for 72 h. A new method of analysis of nifedipine in plasma and faeces using gas chromatography with mass-selective detection (GCMS) was employed. RESULTS: Dissolved nifedipine was found to enter the systemic circulation completely along the intestine, being absorbed from jejunum to colon. Absorption was less rapid from the colon than from the upper part of the gut, but this was not associated with a decrease in absorption and/or bioavailability: Absolute bioavailability, calculated from the normalised AUC values, ranged from 42 to 56%, and bioavailability relative to oral solution was 100 to 126% (medians of the application sites). CONCLUSION: The absence of an absorption window in the intestinal tract suggests that nifedipine is well suited for use in controlled-release formulations.

Adult↗
PubMed1996

Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.

Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethylation and phenacetin 0-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/caffeine ratio, and several metabolite ratios from spot urine sampled 6 h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r= 0.584-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazine-N-acetylation in vitro. In contrast to CYP1A2 parameters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.

Aged↗
PubMed1996

Influence of non-steroidal anti-inflammatory drugs on the binding kinetics of dansylsarcosine to human serum albumin. Stereoselectivity, steric and inductive effects.

The effect of a series of non-steroidal anti-inflammatory drugs (NSAIDs) on the binding kinetics of dansylsarcosine (CAS 72517-44-3, DS), a marker ligand for the benzodiazepine binding site, and human serum albumin (HSA) was studied using the stopped-flow method. Both native (7% glycated) and 25% glycated HSA were used. The binding parameters were determined on the basis of the consecutive model. The DS association rate constant (k2) was 649 +/- 84 s-1 and 375 +/- 13 s-1 for 7% and 25% glycated HSA, respectively. These values were substantially influenced by addition of NSAIDs (molar ratio HSA:NSAID = 2:1), depending on the structure of NSAIDs. The calculated DS dissociation rate constant (k-2) was approximately 20 s-1. this value did not show marked dependence on the degree of glycation or on the presence of NSAIDs at the concentration used. The values were similar to estimates of kd (the displacement rate constant of DS) with the exception of diclofenac (CAS 15307-86-5) where kd was significantly lower, reaching 4.8 +/- 0.4 s-1 and 4.8 +/- 0.6 s-1 vs. k-2 parameters of 14 +/- 2.8 s-1 and 15 +/- 3.7 s-1 for 7% and 25% glycated HSA, respectively. A comparison of the enantiomers R- and S-ibuprofen (CAS 15687-27-1) and the regioisomers fenbufen (CAS 36330-85-5) and ketoprofen (CAS 22071-15-4) showed slight or no stereoslectivity of effects on the DS binding kinetics. However, the binding was influenced by bulk and nature of substituents at the aryl rest of propionic acid. The results obtained for mefenamic acid (CAS 61-68-7) suggest that this NSAID binds to a site of human serum albumin other than site II. Increased concentrations of glycoalbumin, as observed in diabetic patients, are not presumed to have inhibitory effects additional to that of NSAIDs which interact differentially with drugs at site II of HSA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Systematic screening for pharmacokinetic interactions during drug development.

The possible involvement of a new chemical entity in pharmacokinetic drug interactions is an important safety issue. Not all relevant drug combinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications. In this respect the typical approaches currently used, including interaction studies with high risk drugs and compounds frequently given as comedication, or studies involving standard inhibitors and standard substrates are unsatisfactory. A better approach is to characterize drugs according to their effects on the underlying pharmacokinetic processes. Indeed, recent progress in understanding drug interaction mechanisms and in the development and refinement of in vitro test systems enables in many cases experiments to be designed which predict the occurrence of drug interactions. This paper illustrates systematic investigational procedures based on mechanism of interaction. Interaction mechanisms involving drug absorption, distribution, metabolism, and/or excretion are briefly summarized. Detailed proposals are derived which allow identification of the possible role of a new drug in interaction mechanisms for which valid test systems are available. Emphasis is placed on the rational selection of experiments with optimal cost-effectiveness. In vitro methods are integrated in the schemes wherever possible. In addition, it is proposed that pharmacoepidemiological screening, starting in phase II of drug development, be used to identify those relevant drug interactions missed by the mechanism-based approach. As exemplified by several recently discovered interactions it should be possible, by implementation of the proposed procedure, to avoid most serious unexpected adverse effects due to pharmacokinetic drug interactions.

Animals↗
PubMed1995

Determination of free and total 7-hydroxycoumarin in urine and serum by capillary electrophoresis.

A new method for the rapid determination of 7-hydroxycoumarin, the predominant metabolite of coumarin in humans, was developed for analysis in urine and serum, based on separation by capillary electrophoresis, with UV detection at 210 nm. The linear detection range for 7-hydroxycoumarin was 0-50 micrograms/ml while the limit of quantitation was 1 microgram/ml. An internal standard, 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, was utilised for the determination of free 7-hydroxycoumarin, but it was found not to be suitable in the analysis of total 7-hydroxycoumarin present. Urine from two volunteers, who had been administered coumarin, was analysed by both capillary electrophoresis and by HPLC. The results from the two methods were compared and contrasted. The CE method was found to decrease the analysis time in comparison to HPLC analysis, with results available after 1.5 min as compared to 12 min with HPLC. There was no statistical difference between the results determined by either method.

Coumarins↗
PubMed1995

The fate of naringin in humans: a key to grapefruit juice-drug interactions?

The increase of concentrations observed for many drugs when administered concomitantly with grapefruit juice was attributed to inhibition of cytochrome P450 enzymes by naringenin, the aglycone of the grapefruit flavonoid naringin. However, this explanation is equivocal, and formation of naringenin after ingestion of grapefruit juice has not been proved. We investigated renal excretion of naringin, naringenin, and its glucuronides after administration of 20 ml grapefruit juice (621 mumol/L naringin) per kilogram of body weight to six healthy adults. Urine was collected for 24 hours, and flavonoids were measured by HPLC in aliquots with and without glucuronidase pretreatment. Naringin or naringin glucuronides were not found. Naringenin and its glucuronides appeared in urine after a median lag-time of 2 hours and reached 0.012% to 0.37% and 5.0% to 57%, respectively, of the molar naringin dose. In additional investigations, low concentrations (< 4 mumol/L) of naringenin glucuronides, but neither naringin nor naringenin were found in plasma samples from previous grapefruit juice interaction studies, and metabolization of naringin to naringenin occurred during 24 hours of incubation (37 degrees C) in three of five feces samples tested. The data suggest that cleavage of the sugar moiety, presumably by intestinal bacteria, is the first step of naringin metabolism. Naringenin formation is thought to be the crucial step in determination of bioavailability of the compound, which undergoes rapid glucuronidation. The pronounced interindividual variability of naringin kinetics provides a possible explanation for some of the apparently contradictory results of drug interaction studies with grapefruit and naringin.

Adult↗
PubMed1995

Lacking effect of grapefruit juice on theophylline pharmacokinetics.

Grapefruit juice inhibits the biotransformation of several drugs, including caffeine (23% clearance reduction), which is metabolized by the cytochrome P450 isoform CYP1A2. Since CYP1A2 also participates in theophylline biotransformation, a randomized change-over study on a possible interaction between grapefruit juice and theophylline was conducted. Twelve healthy young male nonsmokers were included (median 26 (range 23-30) years, weight 73 (65-85) kg). Theophylline was given as a single dose of 200 mg in solution (Euphyllin 200), diluted by 100 ml of either water or grapefruit juice (751 mg/l naringin). Subsequently, additional fractionated 0.91 of water or juice were administered until 16 hours postdose. Theophylline concentrations in plasma withdrawn up to 24 hours postdose were measured by HPLC, and its pharmacokinetics were estimated using compartment model independent methods. To compare between the 2 treatments, ANOVA based point estimates and 90% confidence intervals (given in parentheses) were calculated for the test (= grapefruit coadministration) to reference (= water coadministration) ratios (Tmax: differences). These were: Cmax 0.90 (0.81-1.00), AUC 1.02 (0.95-1.11), Cmax/AUC 0.88 (0.81-0.95), T 1/2el 1.03 (0.98-1.09), Tmax 0.15 h (-0.11h-0.41 h). Thus, no pharmacokinetic interaction between grapefruit juice and theophylline was observed. This finding is in contrast to the effect of grapefruit juice reported on caffeine metabolism and may be due to the contribution of enzymes other than CYP1A2 to primary theophylline metabolism or to differences in naringin and/or naringenin kinetics between studies.

Absorption↗
PubMed1995

[Pharmacokinetics of a theophylline effervescent tablet].

The theophylline effervescent tablet (Euphyllin quick 200) provides a new acute medication for the treatment of pulmonary obstructive lung diseases. Its pharmacokinetics were determined in 12 healthy male volunteers and compared in a single-dose crossover study to those after administration of an oral solution (Euphyllin 200 ampoule). Based on the primary pharmacokinetic characteristics for rate and extent of absorption, Cmax and AUC, both formulations were bioequivalent.

Adult↗
PubMed1995

Absorption behavior of sulpiride described using Weibull functions.

Deconvolution absorption profiles of oral sulpiride formulations were calculated from plasma concentration-time data obtained in an open, 3-period study with a crossover of the 2 oral formulations in 12 healthy volunteers following single intravenous (100 mg) and oral (2 x 50 mg capsules, 200 mg tablets) application of sulpiride. A model based on 2 Weibull-functions, and applied using NONMEM, described the complex absorption profiles more satisfactorily than a first order absorption model or a model based on a single Weibull-function.

Absorption↗
PubMed1994

Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva.

Several procedures to monitor CYP1A2 activity in vivo by the use of caffeine as a probe have been proposed. They comprise caffeine clearance, based on both plasma and saliva concentrations, urinary metabolite ratios, the 13C-caffeine breath test, and the paraxanthine/caffeine ratio in plasma. The latter method is fast, simple, economical and restricted to one sampling point. In this study, we retrospectively analysed four clinical trials comprising 78 subjects to validate the use of the paraxanthine/caffeine ratios in plasma and saliva for CYP1A2 activity. The validation was done by correlation of these ratios to the systemic caffeine clearance as a reference method. Additionally, urinary metabolite ratios and the caffeine breath test were included in the analysis. The paraxanthine/caffeine ratios in plasma and saliva preferably 5-7 h after administration of caffeine most closely resembled systemic caffeine clearance with correlation coefficients typically higher than r = 0.85. An equation to estimate systemic caffeine clearance from the paraxanthine/caffeine ratios taken at any time within 3-7 h postdose was developed. Correlations of systemic clearance with urinary metabolite ratios and the caffeine breath test were less reliable both in this investigation and in the literature. In conclusion, the paraxanthine/caffeine ratios in plasma and saliva appear a valid and inexpensive method of assessing CYP1A2 activity in vivo. Apparent distribution of CYP1A2 activity for all healthy subjects appeared bimodal in nonsmokers (n = 29) and smokers (n = 17).

Adult↗
PubMed1994

Absorption of ipsapirone along the human gastrointestinal tract.

Isapirone-HCl (5 mg) was administered orally, rectally and locally, by a remote control drug delivery device (HF-capsule) into different segments of the gastrointestinal tract, to four young healthy male adults. The relative systemic bioavailability of the drug from the colon and rectum was 2-3-fold greater than that from the upper gastrointestinal tract. This supports a rationale for a prolonged-release formulation.

Administration, Oral↗
PubMed1993

Biotransformation of methylxanthines in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Allocation of metabolic pathways to isoforms and inhibitory effects of quinolones.

V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2, P450IIB1, human P450IA2, and rat liver epithelial cells expressing murine P450IA2 were used to allocate metabolic pathways of methylxanthines to specific isoforms and to test the suitability of such cell lines for investigations on drug interactions occurring at the cytochrome expressed. The cell lines were exposed to caffeine and/or theophylline and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. The results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity. Addition of the quinolone antibiotic agents pipemidic acid or pefloxacin, both known to inhibit caffeine metabolism in vivo and in human liver microsomes, reduced formation rates of all metabolites of caffeine in cells expressing rat and human P450IA2. Theophylline was mainly metabolized via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1.

Animals↗
PubMed1993

Effect of pretreatment with the selective beta 1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and beta-adrenoceptor subtype specific occupancy of celiprolol in healthy man.

The cardiovascular effects at rest and during exercise and beta 1- and beta 2-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p.o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p.o., using a placebo-controlled, 2-way cross-over design. The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median beta 1-RRA and beta 2-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to beta 1-adrenoceptors, moderately to beta 2-adrenoceptors, acts as beta 1-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect beta 1-adrenergic agonism, but which might reflect beta 2-adrenergic agonism.

Adult↗
PubMed1993

Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man.

1. The effects of grapefruit juice and naringenin on the activity of the human cytochrome P450 isoform CYP1A2 were evaluated using caffeine as a probe substrate. 2. In vitro naringin was a potent competitive inhibitor of caffeine 3-demethylation by human liver microsomes (Ki = 7-29 microM). 3. In vivo grapefruit juice (1.2 l day-1 containing 0.5 g l-1 naringin, the glycone form of naringenin) decreased the oral clearance of caffeine by 23% (95% CI: 7%-30%) and prolonged its half-life by 31% (95% CI: 20%-44%) (n = 12). 4. We conclude that grapefruit juice and naringenin inhibit CYP1A2 activity in man. However, the small effect on caffeine clearance in vivo suggests that in general the ingestion of grapefruit juice should not cause clinically significant inhibition of the metabolism of other drugs that are substrates of CYPIA2.

Adult↗
PubMed1993

Quinolone antibacterial agents: relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2.

The inhibitory effect of 44 quinolone antibacterials and derivatives (common structure, 4-oxoquinoline-3-carboxylic acid) on cytochrome P450 isoform CYP1A2 activity was tested using human liver microsomes and caffeine 3-demethylation as a specific test system for this enzyme. By direct comparison of molecules differing structurally in only one position, the following structure-activity relationships were found. 3'-Oxo derivatives had a reduced or similar activity and M1 metabolites (cleavage of piperazinyl substituent) had a greater inhibitory activity, compared with the parent molecule. Alkylation of the 7-piperazinyl substituent resulted in a reduced inhibitory potency. Naphthyridines with an unsubstituted piperazinyl group at position 7 displayed a greater inhibitory potency than did corresponding quinoline derivatives. Derivatives with a fluorine substitution at position 8 had only a minor effect. Molecular modeling studies with inhibitors and caffeine showed that it is possible to explain the potency of the quinolones to inhibit CYP1A2 on a molecular level. The keto group, the carboxylate group, and the core nitrogen at position 1 are likely to be the most important groups for binding to the active site of CYP1A2, because the molecular electrostatic potential of all inhibitors is very similar to that of caffeine in these regions. The presence of a piperazinyl substituent, however, seems to be no prerequisite for inhibitory potency. Finally, an equation to estimate the potency to inhibit CYP1A2 was developed by quantitative structure-activity relationship analysis.

4-Quinolones↗
PubMed1992

Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms.

Primary steps in the metabolism of caffeine and theophylline are cleavage of methyl groups and/or hydroxylation at position 8, mediated by cytochromes P450. V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2 and P450IIBI and human P450IA2 and rat liver epithelial cells expressing murine P450IA2 were used to overcome problems arising in the proper allocation of metabolic pathways to specific isoforms by conventional techniques. These cell lines were exposed to caffeine and/or theophylline, and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. Theophylline was metabolized mainly via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1. These results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity.

Animals↗