Prediction of Plasma Concentration-time Profiles of Drugs in Humans from Animals Following Oral Administration: An Allometric Approach.

BACKGROUND: Allometric scaling is regularly used for the prediction of human pharmacokinetic (PK) parameters from animal PK studies. The predicted human PK parameters can also be used for the prediction of plasma concentration-time profiles in humans. OBJECTIVES: The main objective of this work is to predict human concentration-time profiles of drugs (one-compartment model) following oral administration using animal oral pharmacokinetic parameters. METHODS: Six drugs from the literature were chosen that were described by one-compartment model in both humans and animals following oral administration. Pharmacokinetic parameters such as oral clearance, oral volume of distribution of the central compartment, time to reach maximum plasma concentration, absorption rate constant, and half-life in humans were predicted from animals using allometric scaling. These predicted human pharmacokinetic parameters were then used to predict human plasma concentrations-time profiles of drugs. RESULTS: The results of this study indicate that the proposed method can be used to predict human plasma concentrations- time profiles of drugs with reasonable accuracy (≤50% prediction error). CONCLUSIONS: Given the complexity in the pharmacokinetics of oral drugs there remains some uncertainty in this entire exercise. One can minimize the prediction error by experience in allometric scaling, scientific judgment, and unconventional or innovative thinking.

A simple chromatographic method for determining norfloxacin and enoxacin in pharmacokinetic study assessing CYP1A2 inhibition.

We developed a simple assay method for the determination of serum and urine norfloxacin and enoxacin using reversed-phase high-performance liquid chromatography and perchloric acid precipitation for sample pre-treatment. Optimized conditions can permit detection of norfloxacin and enoxacin in the same chromatogram, so either compound can be used as an internal standard for another determinant. Supernatants of the precipitated samples were analyzed by the octadecylsilyl silica-gel column under ambient temperature and an ultraviolet wavelength of 272 nm. A mobile phase solvent consisting of 20 mm sodium dihydrogenphosphate (pH 3.0) and acetonitrile (85:15, v/v) was pumped at a flow rate of 1.0 mL/min. The calibration curves for norfloxacin and enoxacin at a concentration of 62.5-1000 ng/mL for serum and 250-4000 ng/mL for urine were linear (r > 0.9997). The recoveries of norfloxacin and enoxacin from serum and urine were >94% with the coefficient of variations (CV) <5%. The CVs for intra- and inter-day assay of norfloxacin and enoxacin were <4.2 and <5.5%, respectively. This method can be applied to the pharmacokinetic study of norfloxacin and enoxacin after repeated administration to assess changes in CYP1A2 activity in healthy subjects.

Exploring Mn-doped ZnS quantum dots for the room-temperature phosphorescence detection of enoxacin in biological fluids.

While most research works focus on the development of quantum dots (QDs)-based fluorescence sensors, much less attention is paid to the phosphorescence properties of QDs and their potential for phosphorescence detection. In this work, the phosphorescence property of Mn-doped ZnS QDs is explored to develop a novel room-temperature phosphorescence (RTP) method for the facile, rapid, cost-effective, sensitive, and selective detection of enoxacin in biological fluids. The Mn-doped ZnS QDs-based RTP method reported here does not need the use of deoxidants and other inducers and allows the detection of enoxacin in biological fluids without interference from autofluorescence and the scattering light of the matrix. The Mn-doped ZnS QDs offer excellent selectivity for detecting enoxacin in the presence of the main relevant metal ions in biological fluids, biomolecules, and other kinds of antibiotics. Quenching of the phosphorescence emission due to the addition of enoxacin at 1.0 microM is unaffected by 5000-fold excesses of Na (+) and 10000-fold excesses of K (+), Mg (2+), and Ca (2+). Amino acids such as tryptophan, histidine, and l-cysteine at 1000-fold concentration of enoxacin do not affect the detection of enoxacin. Glucose does not affect the detection at 10000-fold concentration of enoxacin. Typical coadministers (mainly other types of antibiotics) such as ceftezole, cefoperazone, oxacillin, and kalii dehydrographolidi succinas are permitted at 50-, 10-, 100-, and 50-fold excesses, respectively, without interference with the detection of enoxacin. The precision for 11 replicate detections of 0.4 microM enoxacin is 1.8% (RSD). The detection limit for enoxacin is 58.6 nM. The recovery of spiked enoxacin in human urine and serum samples ranges from 94 to 104%. The developed Mn-doped ZnS QDs-based RTP method is employed to monitor the time-dependent concentration of enoxacin in urine from a healthy volunteer after the oral medication of enoxacin. The investigation provides evidence that doped QDs are promising for RTP detection in further applications.

HPLC determination of enoxacin, ciprofloxacin, norfloxacin and ofloxacin with photoinduced fluorimetric (PIF) detection and multiemission scanning: application to urine and serum.

The fluorescence emission of the fluoroquinolones enoxacin (ENO), ciprofloxacin (CIPRO), norfloxacin (NOR) and ofloxacin (OFLO) notably increased by UV irradiation during few minutes, in ethanolic-water medium. An HPLC method has been developed, for the determination of these fluoroquinolones, based in the separation of the formed irradiation photoproducts. Optimization of the analytical wavelengths has been carried out by fast multiemission scanning fluorescence detection. The highest sensitivity has been found when measuring at emission wavelengths of 407 and 490 nm, for ENO and OFLO, respectively, and at 444 nm for both NOR and CIPRO (exciting at 277 nm). According to the criterium of Clayton, using 0.05 as false positive and false negative error assurance probabilities, detection limits of 7.3, 6.0, 6.3 and 14.5 ng/mL, for ENO, NOR, CIPRO and OFLO, respectively, have been found. Urine and serum samples have been successfully analyzed, with recovery values ranging among 99-97% and 98-103%, for urine and serum, respectively.

Selective separation and simultaneous determination of trace levels of five types of fluorinated quinolone drugs by thin-layer chromatography/fluorescence densitometry.

This paper reports the determination of trace levels of 5 types of fluorinated quinolone drugs, i.e., ciprofloxacin, norfloxacin, enoxacin, pefloxacin, and ofloxacin, by thin-layer chromatography (TLC)/fluorescence densitometry. The new analytical method uses 2-step TLC development, selective separation, and simultaneous determination of the 5 drugs. The method was also applied to the determination of recoveries of standards of the 5 drugs in plasma and urine samples. The results show that the method has a wide linear range, high repeatability, and good stability.

Reversed-phase high-performance liquid chromatographic determination of enoxacin and 4-oxo-enoxacin in human plasma and prostatic tissue. Application to a pharmacokinetic study.

A simple high-performance liquid chromatographic method has been developed for the simultaneous determination of enoxacin and 4-oxo-enoxacin in plasma and prostatic tissue. The work-up procedure involves a liquid-liquid extraction step followed by isocratic chromatography on a reversed-phase analytical column, with ultraviolet absorbance detection (lambda = 340 nm). Using a mobile phase of 20.9% (v/v) acetonitrile buffer (pH 2.1), adequate retention time and separation among the analytes has been obtained using tetrabutylammonium hydroxide included in the eluent. Retention times are 5.2 min for enoxacin, 6.8 min for pefloxacin and 12 min for 4-oxo-enoxacin. For plasma and prostatic tissue, the precision of the assay was below 9%. The percent recovery from the nominal values for accuracy ranged from 94 to 108%. The limits of quantitation were 20 ng/ml for plasma and 50 ng/g for tissue (precision < 18%). The detection limits were 10 ng/ml and 25 ng/g, respectively. The calibration curves were linear from 20 to 1000 ng/ml for plasma and from 50 to 2500 ng/g for tissue. In plasma, the extraction recoveries averaged 52% for enoxacin and 63% for 4-oxo-enoxacin. In prostatic tissue, they were 57 and 76% for the two analytes, respectively. This method has been employed for the determination of enoxacin and 4-oxo-enoxacin in plasma and prostatic tissue samples from patients following repeated oral administration of enoxacin (400 mg twice a day for four days).

Characterization and stability of various liposome-encapsulated enoxacin formulations.

The necessity for antibacterial agents with greater intracellular efficacy has led to the development of endocytosable drug carriers such as liposomes. Enoxacin was selected as a model drug incorporated in various liposome formulations as a therapeutic dosage form using the ethanol injection method and freeze-drying. Liposomal behavior after preparation and stability test was characterized by determining the physicochemical properties of enoxacin encapsulation percent, vesicle size and turbidity. The non-phospholipid formulation of stratum corneum liposomes showed the highest encapsulation efficiency after preparation among nine liposomal formulations. The addition of dissacharides in liposomes also enhanced the encapsulation of enoxacin due to the protection of phospholipid bilayers during the freeze-drying process. The liposomes with negatively charged component and dissacharides showed lower enoxacin leakage after five weeks of storage at 45 degrees C, suggesting these formulations have high stability in long-term storage. The negative liposomes showed a different behavior than others in their decrease of size and turbidity during storage, possibly due to high surface charges of the negative formulation. Cholesterol stabilized bilayers interacted with plasma and high density lipoprotein (HDL) retained enoxacin in the vesicles. Nevertheless, liposomes with cholesterol caused a hydrolysis problem after incubation with normal saline. The formulation with trehalose not only showed high stability in storage but also in plasma and HDL. This suggested trehalose was useful to incorporate with phospholipids to produce a highly encapsulated and stabilized liposomes of enoxacin. This study also demonstrated that thought is required in utilizing turbidity as a direct index of liposomal vesicle size.

Circadian variation in enoxacin-induced convulsions in mice coadministered with fenbufen.

Susceptibility to enoxacin (80 mg/kg, p.o.)-induced convulsions was examined in mice coadministered with fenbufen (100 mg/kg, p.o.) over 24 hr at 3-hr intervals (light 7:00-19:00 hr). There was a marked circadian variation in the incidence of clonic and tonic convulsions and mortality. The susceptibility to enoxacin was higher around 15:00-18:00 hr and lower around 3:00-9:00 hr; the 50% clonic convulsive dose (CD50) at 9:00 and 15:00 hr was 95.0 and 56.5 mg/kg, respectively, its ratio being 1.64. Under these conditions, brain enoxacin level at 15:00 hr was increased 2.43-fold over that at 9:00 hr 30 min after enoxacin administration. Thus, the change of brain enoxacin may contribute to one of the causes of the above circadian variation.

Relation between plasma and saliva concentrations of enoxacin, ciprofloxacin, and theophylline.

To assess the reliability of predicting plasma concentrations of enoxacin, ciprofloxacin, and theophylline from drug concentrations in saliva, six healthy volunteers received single oral doses of enoxacin, ciprofloxacin, and theophylline administered in combination on each of four separate study days, with different, doses separated by at least 5 days. Drug concentrations were determined by a newly developed high-performance liquid chromatography (HPLC) assay, which could measure simultaneously all three drugs in plasma or saliva. Saliva data from the postabsorptive phase after drug administration were used to minimize the effects of variation in absorption. There were good correlations between saliva and plasma concentrations of enoxacin, ciprofloxacin, and theophylline (r = 0.91, 0.88, and 0.98, respectively). The mean (+/-SD) saliva-to-plasma (S/P) ratio for theophylline was 0.63 +/- 0.06 with a coefficient of variation (CV) of 7.9 +/- 2.7%. In contrast, the S/P ratios and CV values for enoxacin and ciprofloxacin were 0.72 +/- 0.21 and 28.9 +/- 11.1%, and 0.58 +/- 0.15 and 25.3 +/- 6.7%, respectively. Because of the large inter- and intraindividual variability, saliva concentrations of enoxacin and ciprofloxacin are not reliable for predicting plasma concentrations. However, saliva may be used reliably for predicting plasma concentrations of theophylline.

Distribution kinetics of enoxacin and its metabolite oxoenoxacin in excretory fluids of healthy volunteers.

The distribution kinetics of enoxacin and its main metabolite oxoenoxacin in excretory fluids was investigated in 11 healthy volunteers. A single intravenous dose of 428 mg of enoxacin was given as a 1-h infusion. Serial samples of plasma, urine, saliva, nasal secretions, tears, and sweat were drawn and analyzed for enoxacin and oxoenoxacin by reversed-phase high-pressure liquid chromatography. Large differences in the concentration-time profiles of the excretory fluids analyzed were observed. Nasal secretions exhibited the highest enoxacin exposure, as assessed by the area under the concentration-time curve. Excretory fluid/plasma area under the concentration-time curve ratios were found to be 1.67 +/- 0.36 for nasal secretions, 0.76 +/- 0.28 for saliva, 0.25 +/- 0.07 for sweat, and 0.23 +/- 0.11 for tears. The elimination half-life of enoxacin from sweat (8.27 +/- 2.63 h) was significantly longer than that for plasma (5.10 +/- 0.46 h). Oxoenoxacin was detected in urine and saliva and exhibited a higher renal clearance and a lower saliva exposure than the parent compound. In contrast to that of the metabolite, distribution of enoxacin in saliva was found to be time and pH dependent. In conclusion, our study revealed considerable differences in the distribution kinetics of enoxacin among various excretory sites. Because of distinct acidic and basic properties, the anionic oxometabolite significantly differs from the zwitterionic parent compound in its distribution characteristics.

Simultaneous determination of theophylline, enoxacin and ciprofloxacin in human plasma and saliva by high-performance liquid chromatography.

A simple reversed-phase high-performance liquid chromatographic method has been developed for the simultaneous determination of theophylline, ciprofloxacin and enoxacin in plasma and saliva. The biological fluid samples were extracted with methylene chloride-isopropyl alcohol prior to isocratic chromatography on a Waters C18 mu Bondapak column. Ultraviolet detection was carried out at 268 nm. The assay is linear for ciprofloxacin and enoxacin (0.05-10 micrograms/ml), and theophylline (0.1-20 micrograms/ml). The assay can be used to investigate the interaction of these two fluoroquinolones with theophylline.

Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition.

Certain fluoroquinolone antibiotics affect theophylline (THEO) disposition by inhibition of its metabolism, yet no studies to date have investigated the relationship between fluoroquinolone plasma concentration and THEO pharmacokinetics. The effects of two fluoroquinolones, enoxacin (ENOX) and ciprofloxacin (CIPRO), have been studied in male Sprague-Dawley rats (n = 33-46) at steady state plasma concentrations of 0-33 mg.l-1, achieved by supplementing an intravenous bolus dose with a constant rate infusion. The effects of steady state ENOX and CIPRO plasma concentrations on the clearance of THEO determined after an intravenous bolus dose of 6 mg.kg-1 were described using a competitive inhibition model. The model consisted of two components, one describing a residual component of THEO clearance, which was unaffected by fluoroquinolone, the other describing the non-linear reduction of THEO clearance by fluoroquinolone. The residual clearance estimated from the model was comparable to renal clearance for THEO in the rat. The potency of each fluoroquinolone was characterised by a Ki value, the concentration reducing THEO clearance by 50% of the maximum change. These values were 4.7 microM and 16.3 microM for ENOX and CIPRO, respectively. Thus, in this study, ENOX was found to be a more potent inhibitor of THEO clearance than CIPRO. The method allowed direct in vivo comparison of potency between different fluoroquinolones, as pharmacokinetic differences, such as clearance, volume of distribution and bioavailability, were 'designed out.'

Determination of lomefloxacin in human plasma by solid-phase extraction and high-performance liquid chromatography with UV detection.

A high-performance liquid chromatographic method for the determination of lomefloxacin in human plasma has been developed and validated. A solid-phase extraction procedure was used to isolate lomefloxacin from the biological matrix prior to the quantitative analysis. The compound was separated on a Vydac anion-exchange column using acetonitrile-phosphate buffer (pH 7.0) as the mobile phase and quantified by measuring its UV absorbance at 280 nm. The lower limit of detection for the analyte was 0.05 micrograms ml-1. Enoxacin was used as the internal standard. The calibration graph of the method was linear from 0.1 to 10 micrograms ml-1 of lomefloxacin in human plasma. This procedure is suitable for pharmacological and pharmacokinetic studies of lomefloxacin.

Accumulation of new quinolones in the blood of elderly patients.

The correlation between serum levels of five new quinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin and lomefloxacin), age and 24 h creatinine clearance was studied in 180 patients. One of five new quinolones was orally administered, before transurethral resection of the prostate, at the dosage of 200 mg three times daily for 3 consecutive days. Serum levels were checked 5.5 h or about 17 h after the final administration. Creatinine clearance was found to be negatively correlated with aging (P < 0.001). After oral administration, the level of certain accumulated new quinolones in serum increased with the age of patients (P < 0.001-0.1). This tendency was more marked for ofloxacin, lomefloxacin and enoxacin than for ciprofloxacin and norfloxacin. The investigators concluded that the level of accumulated new quinolones in serum with aging is correlated to the 24 h urinary excretion rate of each new quinolone. These results indicate that ofloxacin, lomefloxacin and enoxacin, which have higher 24 h urinary excretion rates, should be administered at lower doses according to the age of the patient, in order to prevent adverse reactions.

Simultaneous assay of fluoroquinolones and theophylline in plasma by high-performance liquid chromatography.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of theophylline in plasma simultaneously with either ciprofloxacin, enoxacin or norfloxacin has been developed. It involves extraction of plasma with chloroform-isopropanol or dichloromethane-isopropanol prior to chromatography on a Spherisorb ODS2 column. The mobile phase is 15% acetonitrile in a phosphate buffer (pH 3.0) containing tetrabutylammonium hydrogen sulphate (4.4 mM) as an ion-pairing agent. Ultraviolet detection is carried out at 280 nm. Run time is less than 10 min for all three separations. The assays have been used to determine the effect of plasma concentrations of fluoroquinolone on theophylline clearance.

Determination of ofloxacin in human serum by high-performance liquid chromatography with column switching.

The chromatographic behaviour of ofloxacin on various sorbents, including ODS, C8, C1, nitril, phenyl and tert,-butyl, as stationary phases was investigated and a high-performance liquid chromatography (HPLC) assay was developed for the determination of ofloxacin in serum. The serum samples were directly introduced onto an HPLC column after filtering through a Morcut II membrane filter to remove proteins. The filtrate was concentrated on a pre-column using a phenyl stationary phase and was then introduced to an analytical column with an ODS stationary phase by column switching. Ofloxacin and enoxacin as an internal standard were detected by ultraviolet absorbance at 300 nm. Determination was possible for ofloxacin over the concentration range 50-2000 ng/ml; the limit of detection was 20 ng/ml. The recovery of ofloxacin added to serum was 88.8-101.7% with a coefficient of variation of less than 5.2%. This method is applicable to pharmacokinetic studies of patients after treatment with ofloxacin.

The possible mechanism of interaction between xanthines and quinolone.

To clarify the mechanism of interaction between theophylline and enoxacin, the effects of enoxacin and its metabolite, 4-oxo-enoxacin, on the disposition of new xanthine derivatives, 1-methyl-3-propylxanthine (MPX) and 3-propylxanthine (enprofylline), as models of theophylline have been investigated in rats. Pretreatment with enoxacin significantly delayed the elimination of MPX from plasma. No significant change in the volume of distribution of MPX was observed in the presence of enoxacin, but the total body clearance of MPX was significantly decreased by approximately 60 and 80% after pretreatment with 25 and 100 mg kg-1 of enoxacin, respectively. The amount of the decrease in total body clearance depended on the dose of enoxacin. 4-Oxo-enoxacin had little or no effect on MPX disposition. A newly developed quinolone, NY-198, which does not affect the disposition of theophylline, also did not affect the disposition of MPX. Enoxacin also had no effect on the disposition of enprofylline. These results indicate that the mechanism for decrease in theophylline clearance induced by enoxacin may not be due to its metabolite, 4-oxo-enoxacin, but to enoxacin itself, and that enoxacin does not inhibit solely the elimination process depending on cytochrome P450 isoenzyme for N-demethylation. It is likely that enoxacin has no influence on the renal excretion of xanthines.

[The penetration of ofloxacin and enoxacin into the alveolar spaces in rats].

Ofloxacin (OFLX) or Enoxacin (ENX) was intramuscularly administered at a dose of 100 mg/kg to rats (normal and pneumonia model). Bronchoalveolar lavage (BAL) was performed at 30 min after administration and concentrations of OFLX or ENX in the recovery fluid were determined. Total recovery amounts of OFLX from 10 BAL procedures were 64.7 +/- 18.7 micrograms in the normal group and 126.5 +/- 16.1 micrograms in the pneumonia group, and the amounts of ENX were 15.6 +/- 4.6 micrograms in the normal group and 32.8 +/- 6.1 micrograms in the pneumonia group. Regarding the ratio of total recovery amounts in BAL to serum concentrations of OFLX or ENX, the pneumonia group was higher than the normal group and the ratio of OFLX was higher than that of ENX. Regarding the ratio of total recovery amount in BAL to the amount in lung parenchyma, the ratio of OFLX was higher than that of ENX, but there was no significant difference between the normal group and the pneumonia group in the ratio of OFLX or ENX. With regard to the ratio of the amount of OFLX or ENX in lung parenchyma to their serum concentrations, the ratio was higher in the pneumonia group than in the normal group, but there was no significant difference between OFLX and ENX. Based on the above results, it was concluded that the permeability of OFLX into epithelium of blood capillary is the same as that of ENX, but the permeability of OFLX into alveolus epithelium is superior to that of ENX.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and bioavailability of intravenous-to-oral enoxacin in elderly patients with complicated urinary tract infections.

The pharmacokinetics of oral fluoroquinolone antibiotics in normal volunteers have been studied extensively; however, limited patient data exist. Enoxacin steady-state pharmacokinetics and bioavailability were determined following repeated 400-mg intravenous (i.v.) and oral dosing by using compartmental and noncompartmental methods in 10 elderly (mean age, 73.8 years) men with complicated urinary tract infections. Average peak enoxacin concentrations following i.v. and oral dosing were 8.15 and 5.45 mg/liter, respectively. Mean values for major pharmacokinetic parameters (noncompartmental) were similar following i.v. and oral administration, respectively: area under the concentration-time curve from 0 to 12 h, 47.6 and 41.0 mg.h/liter; volume of distribution or volume of distribution/bioavailability, 1.61 and 1.99 liters/kg; total body clearance or total body clearance/bioavailability, 2.58 and 3.01 ml/min per kg; and half-life, 8.2 and 9.1 h. Parameters from analysis of enoxacin plasma concentration data by using a two-compartment pharmacokinetic model also revealed marked similarities between the two administration routes. Enoxacin was highly bioavailable (mean, 86.97%) following oral administration.