Theophylline metabolism affected by mexiletine.
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Adult↗
Biomedical subjects
U Fuhr
Publications and source records attributed to U Fuhr.
Inhibitory potency of quinolone antibacterial agents against cytochrome P450IA2 activity in vivo and in vitro.
Inhibition of cytochrome P450IA2 activity is an important adverse effect of quinolone antibacterial agents. It results in a prolonged half-life for some drugs that are coadministered with quinolones, such as theophylline. The objective of the study described here was to define the parameters for quantifying the inhibitory potencies of quinolones against cytochrome P450IA2 in vivo and in vitro and to investigate the relationship between the results of both approaches. Cytochrome P450IA2 activity in vitro was measured by using the 3-demethylation rate of caffeine (500 microM) in human liver microsomes. The inhibitory potency of a quinolone in vitro was determined by calculating the decrease in the activity of cytochrome P450IA2 caused by addition of the quinolone (500 microM) into the incubation medium. The mean values (percent reduction of activity without quinolone) were as follows: enoxacin, 74.9%; ciprofloxacin, 70.4%; nalidixic acid, 66.6%; pipemidic acid, 59.3%; norfloxacin, 55.7%; lomefloxacin, 23.4%; pefloxacin, 22.0%; amifloxacin, 21.4%; difloxacin, 21.3%; ofloxacin, 11.8%; temafloxacin, 10.0%; fleroxacin, no effect. The inhibitory potency of a quinolone in vivo was defined by a dose- and bioavailability-normalized parameter calculated from changes of the elimination half-life of theophylline and/or caffeine reported in previously published studies. Taking the pharmacokinetics of the quinolones into account, it was possible to differentiate between substances with and without clinically relevant inhibitory effects by using results of in vitro investigations. The in vitro test described here may help to qualitatively predict the relevant drug interactions between quinolones and methylxanthines that occur during therapy.
4-Quinolones↗
Effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine.
A number of quinolone antibacterial agents, particularly enoxacin, pefloxacin, pipemidic acid and ciprofloxacin, are known to decrease the clearance of methylxanthines. The effects of temafloxacin and ciprofloxacin on the pharmacokinetics of caffeine were therefore compared in a 3-way crossover study in 12 healthy young volunteers. Each volunteer received 183mg once-daily doses of caffeine in conjunction with twice-daily placebo, temafloxacin 600mg and ciprofloxacin 750mg in 3 separate phases according to a randomised sequence. A doubling of the area under the plasma concentration-time curve (77.8 vs 31.8 mg/L.h) and terminal-phase half-life (9.7 vs 4.5h) of caffeine were observed in the presence of ciprofloxacin. The magnitude of the reduction in the intrinsic clearance of caffeine produced by ciprofloxacin was greater than that described in the literature for ciprofloxacin and theophylline. This may partly be explained by intertrial differences in dosage and study design. Coadministration of temafloxacin did not have any effect on the pharmacokinetics of caffeine, confirming results of other studies suggesting that this agent does not affect methylxanthine clearance. Accordingly, it appears that restriction of caffeine intake during temafloxacin therapy is not necessary.
Adult↗
Differences in absorption of BAY u 3405 along the human gastrointestinal tract.
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Adult↗
Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf-capsule.
1. The absorption of ciprofloxacin from different regions of the human gastrointestinal tract was investigated in four healthy males using a remote-controlled drug delivery device (hf-capsule). 2. Significant differences in AUC were observed in the control study (oral administration of ciprofloxacin solution without the hf-capsule = 100%) and after release of ciprofloxacin in the jejunum (geometric mean: 37%), the ileum (mean: 23%), the ascending colon (mean: 7%) and the descending colon (mean: 5%), whereas tmax showed no difference for any of the absorption sites. Ciprofloxacin release in the stomach resulted in the greatest AUC (mean: 140%). Thus, it is concluded that the main absorption site of ciprofloxacin is the upper gastrointestinal tract, up to the jejunum. 3. Differences in presystemic metabolism of known drug metabolites along the gut could be excluded, as the pattern of urinary recovery of desethylene-, sulpho-, and oxo-ciprofloxacin and the parent compound was similar for all drug release sites.
Administration, Oral↗
Absorption differences of ciprofloxacin along the human gastrointestinal tract determined using a remote-control drug delivery device (HF-capsule).
The single-dose absorption kinetics of ciprofloxacin in different regions of the human gastrointestinal tract were investigated using a remote-control drug delivery device (HF-capsule). Doses of 180 to 200 mg ciprofloxacin (as a lactic acid solution) were placed in the HF-capsule and administered to four healthy male adults. The position of the HF-capsule in the gastrointestinal tract was checked via radiographic examination. The release of the solution from the HF-capsule was induced by a radio signal. In each volunteer, the solution was released into five different regions of the gastrointestinal tract: the stomach (B), jejunum (C1), ileum (C2), ascending colon (D1), and descending colon (D2). Two control runs (A1, A2), involving oral administration of the solution, were used as a reference for calculation of area under the curve. The oral administration of a conventional 250-mg tablet (A3) was also studied. The plasma concentration of ciprofloxacin and urine concentrations of ciprofloxacin, desethylene- (M1), sulfo- (M2), and oxociprofloxacin (M3) were determined fluorimetrically by high-performance liquid chromatography. Intraindividual comparisons indicated a progressive decrease in the amount of ciprofloxacin absorbed (100 percent = mean of AUCA1 and AUCA2) from the jejunum (-61 percent, median), ileum (-75 percent), colon ascendens (-90 percent), and colon descendens (-95 percent). Absolute amounts of renally excreted ciprofloxacin and metabolites decreased due to the reduced absorption of ciprofloxacin, but the metabolite pattern was unchanged. It is concluded that the main absorption site for ciprofloxacin is the upper part of the intestinal tract (duodenum, jejunum).
Adult↗
Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations.
The inhibitory effects of ciprofloxacin and other quinolone derivatives on the hepatic cytochrome P450-dependent metabolism of caffeine have been investigated in humans. In vivo studies involved an intraindividual comparison of the single-dose kinetics of caffeine before and during quinolone administration in 12 healthy men. Changes of enzymatic caffeine degradation by the quinolones were studied in vitro using human liver microsomes from three donors. Enoxacin and pipemidic acid markedly prolonged caffeine elimination in vivo. A positive correlation exists between the doses of enoxacin or ciprofloxacin and the prolongation (increases) in the caffeine elimination half-life. Decreases in caffeine elimination, using doses of ciprofloxacin in the upper part of the recommended dose range, were approximately 1.5-fold in comparison with untreated control subjects, whereas in the case of enoxacin there was a sixfold change. In vitro results with enoxacin, ofloxacin, ciprofloxacin, and pipemidic acid show a competitive inhibition (Dixon plots) of caffeine 3-demethylation. Ciprofloxacin and enoxacin showed the strongest inhibitory effects in vitro, whereas ofloxacin had the lowest inhibitory effect. These results are qualitatively reflected in the in vivo results; however, the clinical effects may be dependent on pharmacokinetic disposition of the quinolone and this could explain the weak inhibitory action of ciprofloxacin in vivo.
Adult↗
Study of potential kinetic interactions of picumast dihydrochloride and theophylline in vitro and after oral administration in man.
The kinetic interaction of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and theophylline has been studied in vitro (displacement from protein binding) and in vivo in healthy male non-smokers after oral administration. In a randomized, three-way cross-over study, 12 subjects received at weekly intervals either separated or combined single doses of picumast dihydrochloride (10 mg) and theophylline (7 mg/kg b.w.) Picumast and its metabolites were analysed in plasma and urine up to 24 h and theophylline was assayed in plasma during the same time. Theophylline pharmacokinetic parameters like time to peak concentration, peak concentration, elimination half-life, area under the plasma concentration-time curve and oral clearance were not changed after a concomitant dose of picumast dihydrochloride. The combination of theophylline and picumast dihydrochloride revealed no significant changes in the picumast pharmacokinetic parameters t1/2, tmax and CLR. However, Cmax and AUC0-24 decreased significantly by 11% and 7%, resp. Additional theophylline administration significantly increased peak concentration of the intermediate active metabolite M2 by 23% from 7 to 8.6 ng/ml. The absorptive parameters, i.e. time to peak and peak concentration of M1 as well as the AUC calculated from 0-24 h and the renal clearance did not differ in single or combined picumast dihydrochloride administration. A supplementary in vitro study showed no change in plasma protein binding of picumast (100 ng/ml) in the presence of theophylline (20 micrograms/ml) and vice versa. In all volunteers picumast dihydrochloride proved to be safe and well tolerated and treatment was not negatively influenced by theophylline co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Interaction of quinolones with the theophylline metabolism in man: investigations with lomefloxacin and pipemidic acid.
The single-dose pharmacokinetics of theophylline alone and at the end of a five-day treatment period with a new difluorinated quinolone antibacterial, lomefloxacin (400 mg/d) and pipemidic acid (400 mg b.i.d.) were investigated in 12 healthy male volunteers. Concentration of theophylline and its metabolites 1-methylxanthine, 1-methyluric acid, 1.3-dimethyluric acid and 3-methylxanthine were determined in plasma, and (except 1-methyluric acid) in urine by HPLC separation. The elimination half-life of theophylline before quinolone treatment was 5.7 +/- 2.0 h and did not change significantly under coadministration of lomefloxacin (6.2 +/- 2.0 h), whereas with pipemidic acid a marked prolongation (10.8 +/- 2.3 h) occurred. Results without and during coadministration of lomefloxacin showed no detectable 1-methylxanthine in plasma. With pipemidic acid, 1-methylxanthine was observed in the plasma and 1-methyluric acid and 3-methylxanthine were not detected. Lomefloxacin showed only a slight alteration in the metabolite formation of theophylline, whereas pipemidic acid induced marked changes. In contrast to pipemidic acid, no metabolic interaction would be expected under concomitant use of lomefloxacin and theophylline within the recommended dose range for both drugs.
4-Quinolones↗
[Skeletal changes in Down's syndrome. A correlation between radiological and cytogenetic findings (author's transl)].
One hundred and two patients with Down's syndrome aged one day to 17 years were examined radiologically, seven of these repeatedly. Films obtained included the chest in two planes, lateral spine, left hand and pelvis. The following features were noted; the number of paired ribs, ossification centres in the manubrium, height of lumbar vertebral bodies, shortening of the phalanges, bone age and calculation of the acetabula and ilial angle and ilial index. In all patients the chromosomes were examined in order to determine the cytogenetic type. The following features were found to be more common in Down's syndrome than in normals: abnormal ossification of the manubrium (33%), aplasia of the twelfth rib (18%), high lumbar vertebral bodies (50%), brachymesophalangia of the fifth ray (62%) and changes in skeletal maturation (acceleration or retardation in 48%). Changes in the pelvis were typical; with increasing age, the acetabular angle falls and the ilial angle increases. The most striking skeletal changes were found in 84 patients with trisomy 21.
Adolescent↗
CSF pharmacokinetics of ceftazidime in neurosurgical patients with an external ventriculostomy.
In 11 neurosurgical patients (seven women, four men, aged 22-73 years) undergoing external ventriculostomy, serum and cerebrospinal fluid (CSF) pharmacokinetics of ceftazidime (CAZ) administered as a chemoprophylactic agent were evaluated. Concentrations of CAZ in CSF correlated significantly (p less than 0.05) with serum concentrations and with leucocyte counts in CSF. Peak concentrations in CSF (range 0-25.5 mg/l) exceeded the MIC90 of Staphylococcus species in two and of Pseudomonas and Enterobacter species in five of 11 patients. The MIC90 values of the other relevant bacteria causing CNS infections in these patients were surpassed in nine of 11 patients.
Adult↗
The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine.
Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups: (1) absence of GS (non-GS)/rapid acetylator (RA) (N=11); (2) GS/RA (N=8); (3) non-GS/SA (N=11); (4) GS/SA (N=7). Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple-dose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P=0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.
Acetylation↗
[Skeletal manifestations in Down's syndrome. Correlation between roentgenologic and cytogenetic findings].
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Adolescent↗
Quinolone inhibition of cytochrome P-450-dependent caffeine metabolism in human liver microsomes.
Inhibitory effects of the quinolone antibiotics ofloxacin, lomefloxacin, pipemidic acid, ciprofloxacin, and enoxacin on caffeine metabolism were examined in vitro with human liver microsomes of four donors. All drugs competitively inhibited the activity of 3-demethylation, the major pathway of caffeine metabolism. Enoxacin, ciprofloxacin, and pipemidic acid were strong inhibitors exhibiting Ki values between 0.1 and 0.2 mM. Lomefloxacin and ofloxacin had moderate effects with Ki values of 1.2 and 3.6 mM, respectively. The rate of caffeine 7-demethylation (which amounted to about 25% of that for 3-demethylation) was only slightly affected by the quinolones. Minor, but inconsistent, effects were found on 8-oxidation to 1,3,7-trimethyluric acid. The results indicate that the reduction of caffeine clearance by concomitant quinolone application observed in vivo is primarily due to a competitive interaction of the inhibiting quinolones with the cytochrome P-450 isoenzyme(s) mediating caffeine demethylation.
Aged↗