The effect of antacids on the systemic absorption of oral norfloxacin was evaluated in 12 healthy volunteers. Subjects were given each treatment in a balanced sequence at 7-day intervals. Treatments included 400 mg of norfloxacin alone, 400 mg of norfloxacin 5 min after aluminum-magnesium hydroxide (Maalox), Maalox 2 h after 400 mg of norfloxacin, and 400 mg of norfloxacin 5 min after calcium carbonate (Titralac). Blood and urine samples were collected at predetermined time intervals for 24 and 48 h, respectively. Norfloxacin concentrations in plasma and urine were determined by high-pressure liquid chromatography. The area under the plasma concentration-versus-time curve from time zero to infinity and urinary recovery were used to compare the relative bioavailability of norfloxacin with antacids with that of norfloxacin alone. Norfloxacin bioavailability was markedly reduced when subjects received antacid pretreatment. When norfiloxacin was given 5 min after Maalox and Titralac, the bioavailabilities were 9.02 and 37.5%, respectively, relative to that for 400 mg of norfloxacin alone. When Maalox was given 2 h after norfloxacin, maximal concentrations of norfloxacin in plasma occurred between 1 and 1.5 h postdose, and absorption was reduced to a lesser extent, with a relative bioavailability of 81.31%. Norfloxacin concentrations in urine were also reduced as a result of antacid administration. Antacids containing aluminum and magnesium salts and calcium carbonate should be avoided by patients taking norfloxacin.Norfloxacin is a fluoroquinolone antimicrobial agent that is indicated for treating both complicated and uncomplicated urinary tract infections in patients who are candidates for oral therapy. A prerequisite to using oral antimicrobial agents is assurance that the drug will be absorbed. Antacids containing aluminum and magnesium salts may reduce absorption of the fluoroquinolones (3-6). Chelation between these metal ions and the 3-carboxyl and 4-oxo substituents on the quinolone nucleus results in a complex that is more polar and unable to be absorbed (4). Because this interaction may cause markedly reduced bioavailability, its occurrence may lead to therapeutic failures.In this study, the effects of antacid administration on the systemic bioavailability of oral norfloxacin were evaluated. MATERIALS AND METHODSThe study included 12 males between the ages of 18 and 40 years. Written informed consent was obtained. The subjects were determined to be healthy by physical examination, medical history, electrocardiogram, and laboratory tests. They were free of significant physical or psychological abnormalities, drug abuse, and allergies.A balanced, four-period, crossover design was employed. Subjects received each treatment once, and each treatment period was separated by a 7-day washout period. Treatments included 400 mg of norfloxacin, 400 mg of norfloxacin 5 min after 30 ml of aluminum and magnesium hydroxide (Maalox), 400 mg of norfloxacin followed by 30 ml of Maalox 2 h later, and 400 mg of norfloxacin 5 m...

No abstract

Genetic polymorphism in oxidative drug metabolism is perhaps best exemplified in the case of debrisoquine 4-hydroxylase activity, where the incidence of deficient metabolism ranges from 1% to 30% in various populations and this defect is also linked to an impaired ability to metabolize a number of other drugs effectively. Sprague-Dawley (SD) rats possess this activity, but females of the DA strain do not, although total cytochrome P-450 (P-450) levels are similar. We have purified, by using debrisoquine 4-hydroxylase activity as an assay, a minor P-450 to electrophoretic homogeneity from male SD rats and designate this as P-450UT-H. P-450UT-H differs from eight other purified rat liver P-450s as judged by peptide mapping and immunochemical analysis and thus appears to be isozymic with these other P-450s. P-450UT-H exhibited considerably more debrisoquine 4-hydroxylase activity than any of the other purified P-450s and, on a total P-450 basis, more than total microsomal P-450. Antibodies raised against P-450UT-H specifically recognized P-450UT-H and inhibited more than 90% of the debrisoquine hydroxylase activity present in SD rat liver microsomes. The level of P-450UT-H in SD rat liver microsomes accounted for less than 10% of the total P-450, as judged by immunochemical quantitation. These assays also indicated that the level of P-450UT-H in female DA rat liver microsomes is only about 5% of that in male or female SD rat liver microsomes, consonant with the view that deficiency of this form of P-450 is responsible for the defective debrisoquine 4-hydroxylase activity in the former animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Debrisoquine 4-hydroxylase activity is a prototype for genetic polymorphism in oxidative drug metabolism in humans; approximately 10% of Caucasian populations exhibit the poor metabolizer phenotype, and the clearance of at least 14 other drugs has been shown to be deficient in patients exhibiting this phenotype. Antibodies prepared to a cytochrome P-450 shown to be responsible for debrisoquine 4-hydroxylation in rats were found to inhibit the oxidation of debrisoquine and sparteine, encainide, and propranolol, three other drugs suggested to be associated with this phenotype, in human liver microsomes. The antibodies did not inhibit the oxidation of seven other cytochrome P-450 substrates. The antibodies recognized a single polypeptide of Mr 51,000 after combined sodium dodecyl sulfate/polyacrylamide electrophoresis and immunochemical staining of human liver microsomes. The intensity of this band was significantly correlated with debrisoquine 4-hydroxylase activity when liver microsomes from 44 organ donors were examined. Immunoprecipitation of in vitro translation products of total liver RNA revealed major electrophoretic bands corresponding to the cytochrome P-450 in rats and humans. The level of translatable mRNA coding for the debrisoquine-hydroxylating cytochrome P-450 was an order of magnitude less in human liver than in rat liver. The availability of these antibodies provides a biochemical basis for further basic and clinical studies on the role of a particular cytochrome P-450 polymorphism in humans.Genetic polymorphisms contribute in part to the large interindividual differences observed in the oxidation and conjugation of drugs and other compounds (1)(2)(3). Approximately 10% of Caucasians are phenotypic poor metabolizers of the anti-hypertensive drug debrisoquine; these individuals are genotypic homozygous recessive at an autosomal genetic locus controlling the formation of 4-hydroxydebrisoquine, a major urinary metabolite in phenotypic extensive metabolizers (4, 5). Studies with human liver microsomes suggest that poor metabolizers of debrisoquine lack the particular P-450 form that hydroxylates the drug in normal individuals (6).One clinical consequence of debrisoquine hydroxylation deficiency is that poor metabolizers are more sensitive to the hypotensive effects of debrisoquine (7). Moreover, the oxidative metabolism of at least 14 other drugs is impaired in these individuals, suggesting a functional deficiency of one or more P-450 enzymes responsible for the oxidation of a large group of compounds (8). Consequently, patients deficient in debrisoquine hydroxylation can be especially sensitive to the therapeutic or toxic effects of several other drugs because the parent compound is either poorly eliminated by metabolism or shunted to a secondary metabolic pathway, which produces greater amounts of a normally minor but toxic metabolite (9). Deficient metabolizers of debrisoquine can also respond poorly to drugs that have pharmacologically active metabolites (10). The phenotype of debrisoquine...

Systemic beta-blockade after single doses of ophthalmic beta-blockers (one drop in each eye) was investigated in healthy volunteers in two randomized, double-blind, crossover, placebo-controlled studies. beta-Blockade was evaluated by displacement of the bronchodilator (specific airway conductance), positive chronotropic (heart rate), and tremorogenic (finger tremor amplitude) dose-response curve for inhaled isoproterenol. In study 1, 0.5% betaxolol, 0.6% metipranolol, and 0.5% timolol were tested in 16 subjects. Compared with placebo, all beta-blockers resulted in a significant systemic beta-blockade (p greater than 0.05); the increasing order of potency was betaxolol, metipranolol, and timolol. In study 2, 2% butylamino-phenoxy-propanol-acetate (BPPA; a noncardioselective but topically oculoselective drug) and 1% timolol were investigated in 12 subjects. Placebo and BPPA showed no differences (p greater than 0.05), whereas timolol resulted in a significant beta-blockade (p less than 0.05). Topical oculoselectivity is an important aspect of drug safety of beta-blocking eyedrops. Measure of tremor is appropriate to evaluate beta 2-blockade.