Dermatotoxic effects of orally administered ciprofloxacin in sweating and nonsweating animal models

Context: Some drugs, such as ciprofloxacin (CFX), that are excreted in sweat may produce some effects/toxicities in the skin structure. In order to differentiate the dermatotoxic effects of drugs due to excretion in sweat, it is essential to perform simultaneous studies in sweating and nonsweating animal models.

Objective: To determine the dermatotoxic effects of CFX in sweating (goats) and nonsweating (rabbits) animals and to determine whether there is a relationship between dermatotoxicity and the blood CFX concentration.

Materials and methods: CFX was administered orally at the dose rate of 20?mg/kg body weight to goats (n?=?16) and rabbits (n?=?16) for 1 and 2 weeks, while control animals were given vehicle (water). Skin biopsies were taken after 1- and 2-week administration of CFX and processed histologically. Similarly, the CFX concentration in the plasma samples was analyzed by high-performance liquid chromatography (HPLC). Results: Mean ± standard error (SE) epidermal thickness (μm) was 26.2?±?0.2, 38.6?±?2.05, and 37.8?±?1.8 for the control, 1-week-treated, and 2-week-treated goats and 16.06?±?2.39, 50.67?±?6.61, and 34.03?±?4.12 for the control, 1-week-treated, and 2-week-treated rabbits, respectively. Mean ± SE epidermal cell layers were 2.08?±?0.08, 3.42?±?0.16, and 3.25?±?0.21 in the control, 1-week-treated, and 2-week-treated goats and 1?±?0, 3.08?±?0.37, and 1.83?±?0.35 in the control, 1-week-treated, and 2-week-treated rabbits, respectively. Mean?±?SE plasma concentration (μg/mL) of CFX was 0.37?±?0.06 and 0.30?±?0.05 in the 1- and 2-week-treated goats and 0.13?±?0.04 and 0.14?±?0.09 in the 1- and 2-week-treated rabbits, respectively.

Conclusion: Microscopically, increases in epidermal thickness, number of cell layers, and cell infiltration were observed in both sweating and nonsweating animals, indicating that the dermatotoxic effects may not be due to CFX excretion in sweat. No relationship was found between dermatotoxicity and blood CFX concentration in both animal models.     

Calculation of the blister fluid-time history with ciprofloxacin administered orally or by infusion

The drug level-time history was calculated either in the blood compartment or in the blister fluid through the skin, when the drug was administered through various ways: orally with immediate release dosage forms or with controlled release dosage forms, through infusion with a constant rate. These drug-time histories were found to be in good agreement with experimental results shown in the literature, with the immediate release oral dosage forms and with infusion. A numerical model was built, taking into account all the known facts concerned with the pharmacokinetic parameters of the drug, with the kinetics of absorption and elimination, as well as the stage through which the drug is transported from the blood compartment to the blister fluid in the skin, assumed to be governed by transient diffusion with constant diffusivity. A parameter of interest appears with the ratio of the diffusivity and the mean length of tissue over which the diffusional transport takes place.     

The availability of orally administered nortriptyline

Summary The availability of an orally administered drug may be defined as the fraction of the total dose that enters the blood. Three healthy subjects were given identical doses of nortriptyline hydrochloride (NT-HCl) by the oral and intramuscular routes. The availability was assessed by comparing the total areas under the NT plasma concentration-time curves produced by the two methods of administration. The concentrations of NT in plasma and blood were determined by gas chromatography — mass spectrometry and were found to be almost identical. The observed availability of NT in these subjects ranged between 56 and 70% (mean 64%). The availability predicted from the parenteral plasma levels (assuming an average hepatic blood flow of 1.7 l/min) differed from the observed availability in one subject, perhaps because of the known variation in liver blood flow between individuals. The gastrointestinal absorption of NT-HCl was complete, since the recovery of the main metabolite, 10-hydroxynortriptyline, was the same after the two routes of administration. Pharmacokinetic analysis of the data showed that there might exist interindividual differences in the apparent volume of distribution of NT, (V_d). There was no apparent relationship between the variations in availability of NT and steady-state plasma levels or the disposition plasma half-lives of the drug. The calculated (V_d) and (t 1/2) of NT for each subject were in good agreement with those obtained from a previous study of single oral does of NT.     

The pharmacology of chymotrypsin administered by inhalation

The ability of chymotrypsin to reach the limits of the bronchial tree has been studied in cats receiving the enzyme by inhalation as a very fine powder. For this purpose derivatives of chymotrypsin were used which had been labelled with a fluorescent molecule or with [¹³¹I]. Quantitative measurements of the absorption and distribution of inhaled chymotrypsin- [¹³¹I] revealed a rapid removal of radioactivity from the lungs over the first 24 hr. and corresponding excretion of labelled inorganic iodide in the urine. High levels of activity were not attained in the blood or thyroid. Subcutaneous administration of labelled enzyme led to more rapid accumulation of radioactivity in the blood and thyroid. Consideration of these and other results leads to the conclusion that, while some enzyme ascends the respiratory tract by ciliary movement of mucus, a substantial part is absorbed into the lungs and the [¹³¹I] subsequently detached from it.

The changes in tidal air accompanying inhalation of labelled trypsin and chymotrypsin were followed in anaesthetized cats. Trypsin brings about a decrease in tidal air in distinctly lower doses than does chymotrypsin. Prior administration of mepyramine had an antagonistic effect, and it is suggested that the change in tidal air is essentially the result of bronchial spasm.

     

The metabolism of orally administered L-DOPA in Parkinsonism

1. Gas-liquid chromatographic methods were used to measure urinary acidic and alcoholic metabolites of L-DOPA, which had been administered in high oral dosage to patients with postencephalitic and idiopathic Parkinsonism.

2. The output of these compounds was normal before treatment. During drug therapy, large quantities of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were excreted but traces only of 4-hydroxy-3-methoxyphenylethanol. Noradrenaline metabolites showed little change in output other than a small increase in 4-hydroxy-3-methoxymandelic acid.

3. Information was obtained about a number of minor routes of degradation which might be implicated in the therapeutic action of L-DOPA. A raised output of m-hydroxyphenylacetic acid pointed to p-dehydroxylation of dihydroxyphenylacetic acid by gut flora. Evidence of transamination as a minor metabolic pathway was obtained by finding appreciable urinary levels of 4-hydroxy-3-methoxyphenyllactic acid. A keto-acid precursor of this compound may act as competitive inhibitor of an enzyme active in the normal degradation route of tyrosine, p-hydroxyphenylpyruvic acid oxidase, for increased amounts of p-hydroxyphenyllactic acid, the major metabolic derivative of p-hydroxyphenylpyruvic acid, accumulated in the urine during DOPA treatment.

     

口服洛美沙星的人体药物动力学

目的:研究健康志愿者单剂po国产洛美沙星400mg后的药物动力学特征.方法;采用HPCL法测定血清和尿中药物浓度.结果:该药在人体内的转运过程符合二室开放模型,C_(max)为 4.88 mg/L,T_(1/2β)为 7.19 h,Vd和AUC分别为 1.51L/kg和51.03(mg·h)/L,CL为 2.47 d/(min·kg),48h尿药排泄率为75.7%.洛美沙星的人血清蛋白结合率为16.3%.结论:洛美沙星400mg单剂po后血和尿中可迅速达到有效抗菌浓度且持续时间较长.     

Bioavailability of orally administered mesna

The bioavailability of orally administered sodium 2-mercaptoethane sulfonate (mesna, Uromitexan drink ampoules) was tested in 18 healthy probands and in 5 tumor patients. Following single oral administration of 20 or 40 mg/kg mesna, 52.4% and 52.6%, respectively, of the dose were excreted in the urine as reactive thiol groups, the remainder as mesna disulfide (dimesna), the only metabolite of mesna; after i.v. injection of 20 mg/kg mesna, 48.7% of the dose administered appeared as thiol groups in the urine. Not until after 13.1 h (20 mg/kg p.o.) and 18.5 h (40 mg/kg p.o.), respectively, concentration drops below the minimum concentration of 100 micrograms/ml presumed to be still reliably protective. However, the elimination pattern and the time when the threshold concentration is reached are subject to marked individual variation. After i.v. administration of 20 mg/kg mesna and 9 times oral administration of 20 mg/kg mesna (the first dose concurrently with the i.v. injection, thereafter every 4 h), or 7 times oral administration of 20 mg/kg mesna (the first dose again concurrently with the i.v. injection, thereafter every 5 h), the percentage of the total dose administered appearing as thiol groups in the urine averaged 41.9% and 37.6%, respectively, up to 17 or 18 h after the last dose. Comparison of periods covering the same time of the day showed the total amount excreted to be higher on day 2 than on day 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

国产洛美沙星胶囊的人体药物动力学

目的：研究健康志愿者单剂口服国产洛美星胶囊４００ｍｇ后的药物动力学特征。方法：采用ＨＰＬＣ法测定血清和尿中药物深度。结果：该药在人体内的转运过程符合二室放模型,血药峰浓度为４．８８ｍｇ．Ｌ＾－１,消除半衰期为７．１９ｈ,表观分布容积和ＡＵＣ分别为１．５１Ｌ．ｋｇ＾－１和５１．０３ｇ．ｍｇ．Ｌ＾－１,总清除率为２．４７ｍｌ．ｍｉｎ＾－１．ｋｇ＾－１,４８ｈ尿药排泄率为７５．７％。洛美沙星的人血清蛋白     

The analgesic effects and mechanisms of orally administered eugenol

In the present study, the antinociceptive profiles of eugenol were examined in ICR mice. Eugenol administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of eugenol maintained at least for 30 min. Moreover, the cumulative response time of nociceptive behaviors induced by an intraplantar formalin injection was reduced by eugenol treatment during the 2^nd phases. Furthermore, the cumulative nociceptive response time for intrathecal injection of substance P (0.7 μg) or glutamate (20 μg) was diminished by eugenol. Intraperitoneal pretreatment with yohimbine (α2-adrenergic receptor antagonist) or naloxone (opioid receptor antagonist) attenuated antinociceptive effect induced by eugenol in the writhing test. However, methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by eugenol in the writhing test. Our results suggest that eugenol shows an antinociceptive property in various pain models. Furthermore, this antinociceptive effect of eugenol may be mediated by α2-adrenergic and opioidergic receptors, but not serotonergic receptor.     

Basic experiments with clotrimazole administered orally

Summary

A series of experiments was carried out with the antimycotic agent clotrimazole to establish MICs against a number of different yeasts and to estimate its blood levels following oral administration. Marked differences were notedbetween the MIC against A and B serotypes of Candida albicans in its yeast-like cell form, that against Type B being nearly 10-times higher than against Type A. Against the mycelial form, however, the MIC was much lower and there was little difference between the levels for the two serotypes. Clotrimazole administered in oraltabletform appearedtobepoorly absorbed, little being transferred to the blood. Urinary levels were low and large amounts of the drug were detected in the faeces. Serum levels were below MIC levels in all cases examined. Blood levels 3-times as great as those after the same dosage in tablet form were produced when clotrimazole was given in oil solution and even with 250?mg, effective blood levels were achieved and maintained.     

The fate of dienochlor administered orally and dermally to rats

Within four days of receiving a single oral dose (1 mg/kg) of [U-ring-14C]dienochlor [bis(pentachloro-2,4-cyclopentadien-1-yl)] female rats excreted 2 and 88% of the applied 14C in urine and feces, respectively. Metabolites could not be identified and the preponderance of the fecal radioactivity consisted of unextractable 14C-labeled residues. Within 1 day virtually all of the dienochlor had been degraded by rats, with only traces of parent dienochlor in excreta and tissues. After four days only 2% of the applied dose remained in tissues (mainly kidney, liver, and gastrointestinal tract). Pharmacokinetic studies with blood plasma and bile showed dienochlor (and/or its metabolites) to be poorly absorbed. Rats were exposed dermally for 24 hr to [14C]dienochlor formulated as Pentac WP miticide both as an aqueous suspension and as an undiluted wettable powder. Half of the dose adhered to the skin and the other half was found in gauze patches used to protect the treated skin. After a 24-hr exposure over 60% of the radiolabel that adhered to skin was removed by washing with an aqueous soap solution and 86% of this rinsing solution was unmetabolized dienochlor. The dienochlor and its metabolites were transported inefficiently from the application site; only 1% of the applied dose was detected in urine plus feces and less than or equal to 0.2% in tissues. With application rates that simulate field exposure by humans, the actual residue of dienochlor and metabolites in skin (i.e., not removable by washing) is about thirteen times higher following exposure to dienochlor as undiluted wettable powder than as an aqueous suspension.     

Pharmacokinetics of orally administered pentoxifylline in humans

The pharmacokinetics of pentoxifylline was studied in healthy male volunteers following single oral doses of 100, 200 and 400 mg of the drug in solution. Concentrations of the drug and three of its metabolites were determined in plasma. The major urinary metabolite was also determined for 24 hours after dosing. Pentoxifylline was rapidly and extensively absorbed at all doses. Peak plasma concentrations of pentoxifylline occurred between 0.29 and 0.41 hours after dosing. Its metabolites, a secondary alcohol and two homologous carboxylic acids showed tmax values from 0.72 to 1.15 hours. Cmax and AUC values increased in a dose-dependent manner for pentoxifylline and its metabolites over the three dose levels though strict dose proportionality could only be demonstrated for the principal carboxylic acid metabolite. The apparent plasma half-life of pentoxifylline varied between 0.39 and 0.84 hours for the various doses while the apparent half-lives of the metabolites were in the range of 0.96 to 1.61 hours. The major circulating metabolites, the secondary alcohol and carboxypropyl derivative, were at consistently higher plasma concentrations than the parent drug. Two major pathways account for the circulating metabolites of pentoxifylline though oxidation of the parent drug to a carboxylic acid accounts for the formation of the principal urinary elimination product. Because of the pharmacological activities of pentoxifylline, studies are proposed of the pharmacokinetic-pharmacodynamic correlations of pentoxifylline and its metabolites. The present pharmacokinetic results further support the use of a controlled-release dosage form of pentoxifylline for therapy.     

Regional pharmacokinetics of orally administered PET tracers

Positron emission tomography (PET) is currently the most useful imaging technique for noninvasive measurement of drug pharmacokinetics regionally in a variety of tissues. Over the past decade, PET measurements have provided many critical insights about the tissue distribution of several classes of drugs; neuroleptics, antimicrobials, antineoplastics, etc. PET measurements can be performed after any route of drug administration, intravenous, inhalation or oral, however, intravenously administered drugs have been the most extensively evaluated. Studies of orally administered drugs are clearly of great interest; however, formulation issues have precluded widespread applications in these areas. In this report, we discuss the unique problems associated with studying orally administered drugs and review the results of recent studies performed in our laboratory.     

Brain penetration of orally administered sodium pyroglutamate

The absorption and brain penetration of [3H]pyroglutamate was determined after oral administration to rats. Gas-liquid chromatography of the methylated derivatives followed by mass fragmentometry was used to analyse the plasma and brain levels of pyroglutamate. [3H]Pyroglutamate was separated from other labelled compounds by thin layer chromatography. The administration of 500 mg kg-1 [3H]pyroglutamate resulted in a 30-fold increase in plasma levels and a doubling in the brain levels. Over 60% of the cerebral radioactivity was present as [3H]pyroglutamate demonstrating that pyroglutamate is not only well absorbed but also penetrates in significant amounts into the brain.