氧氟沙星在肾功能障碍大鼠唾液中的分布

目的 :研究肾功能障碍时氧氟沙星 (OFLX)在唾液中分布的变化规律。方法 :通过 5 / 6肾摘除术 ,制成大鼠肾功能障碍模型 ,以模拟手术为对照。OFLX( 10mg·kg-1)静脉注射后 ,经时采血及腮腺 (Pr)、颌下腺 (M )唾液。采用HPLC法测定各样品中的OFLX浓度。结果 :肾功能障碍使大鼠OFLX血浆浓度显著增高 ,全身清除率下降约 4 0 %。肾障碍组Pr唾液中浓度明显增高 ,而M唾液中浓度与对照组之间差异无显著性。在肾功能障碍组及对照组 ,消失相的OFLX唾液中浓度及唾液 /血浆浓度比 (S/P比 ) ,在Pr唾液均比M唾液高约 2和 3倍。肾功能正常大鼠的S/P比与Pr唾液中药物浓度之间呈良好正相关。结论 :OFLX在大鼠唾液中的分布存在腺差。肾功能低下 ,导致了OFLX向Pr唾液中的移行性增大 ,但对M唾液的影响不明显。而OFLX向Pr唾液中分布的量与该唾液中药物浓度有关。     

Salivary excretion of mexiletine after bolus intravenous administration in rats.

Salivary excretion of mexiletine was investigated following bolus intravenous administration (10 mg kg-1) in rats. Parotid and mandibular saliva was collected separately by stimulating salivation with constant rate infusion of pilocarpine (3 mg kg-1 h-1). The mexiletine levels in blood plasma and parotid and mandibular saliva declined biexponentially with time in almost parallel fashion. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva. Significant correlations were observed when all data relating mexiletine concentration in plasma and saliva were included (P less than 0.001). The saliva/plasma drug concentration ratios (S/P ratios) did not vary to a large extent (0.56 +/- 0.10 for parotid saliva, 0.21 +/- 0.06 for mandibular saliva), but there was a consistent tendency for the higher plasma drug levels in the distribution phase to produce relatively high S/P ratios for both parotid and mandibular saliva. Moreover, the plasma mexiletine levels calculated by the equation of Matin et al (1974) employing the observed values for the saliva drug level, saliva pH and free fraction of mexiletine in plasma were significantly higher than the observed drug levels. Therefore, it is suggested that the salivary excretion of mexiletine could not be explained quantitatively by simple, passive secretion based on pH-partition theory.     

Mandibular and parotid salivary excretion of procainamide and N-acetylprocainamide after intravenous administration of procainamide to rats

Flow rate, protein level and pH of mandibular and parotid saliva samples in rats were almost stabilized 2 h after induction of salivation with pilocarpine (9.0 mg h-1 kg-1). Salivary excretion profiles of procainamide, 50 mg kg-1 i.v., and its metabolite N-acetylprocainamide (NAPA) were then investigated. Plasma and salivary procainamide levels declined bi-exponentially with time almost in parallel. Salivary procainamide levels (Y) from both types of gland were correlated with the plasma level (X) over a wide concentration range [Y = 0.108X + 1.96 (r = 0.795) for mandibular and Y = 0.917X (r = 0.974) for parotid glands]. The mean saliva to plasma concentration ratio (S/P ratio) was significantly higher in parotid (0.974 +/- 0.243) than in mandibular (0.284 +/- 0.119) saliva samples. Similar correlations and S/P ratios were observed for NAPA. Procainamide and NAPA mean S/P ratios for saliva from both glands were fairly consistent with the calculated value according to the pH-partition hypothesis.     

Dependency of salivary excretion of mexiletine on the plasma concentration in rats

Abstract— The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2·7 or 16·1 mg kg^?1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 μg min^?1 kg^?1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 μg kg^?1 min^?1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0·259 + 0·123 and 1·616 ± 0·475 μg mL^?1, respectively, within the first 1–2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0·001 or 0·01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0·475 + 0·160) than that (0·386±0·131) at the low steady-state (P < 0·05). The S/P ratio for mandibular saliva at the high (0·204 ± 0·060) steady-state was also greater than that at the low (0·158 ± 0·050) steady-state (P < 0·01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.     

Mandibular and Parotid Salivary Levels of Indomethacin Following Intravenous Administration to Rabbits

Indomethacin was measured in mandibular and parotid saliva, obtained from separate cannulas in the salivary ducts, after bolus intravenous administration (15 mg/kg) to male white rabbits that were stimulated for salivation with pilocarpine given subcutaneously. There was a significant correlation between each salivary drug concentration and plasma drug concentration. Saliva to plasma drug concentration ratio (S/P ratio) and pH were higher in mandibular saliva than in parotid saliva. These gland specific differences were in contrast with the previously reported differences in dogs. Matin's equation was found to predict approximately the mean observed S/P ratio of indomethacin for each saliva sample.     

Biological Monitoring of Diazinon Exposure Using Saliva in an Animal Model

Alternative biological monitoring methods are currently being pursued to better quantify pesticide exposures. In this study, the feasibility of using saliva as a tool for measuring diazinon exposure was determined in an animal model. Male Spraque-Dawley rats were dosed with 1 or 10 mg/kg diazinon by bolus intravenous injection. Time-matched saliva and arterial blood samples were collected from 10 to 250 min post administration. Diazinon was distributed and eliminated rapidly in rats following intravenous (iv) bolus injection, according to a two-compartmental pharmacokinetic analysis. Salivary concentration of diazinon showed a strong correlation with plasma concentration of diazinon. The saliva/plasma (S/P) concentration ratio of diazinon was not affected by administered dose, sampling time, or salivary flow rate, suggesting that salivary excretion of diazinon in rats is fairly constant. Diazinon concentrations in saliva were consistently lower than those in arterial plasma. The mean S/P concentration ratios of diazinon were 0.16 and 0.13 for 1 and 10 mg/kg iv bolus doses, respectively. It is most likely that the incomplete transfer of diazinon from plasma to saliva is due to protein binding of diazinon in plasma. If the protein-unbound fraction of diazinon in plasma is used to calculate the S/P ratio, the S/P concentration ratio of diazinon is close to unity. The results from this study support the conclusion that diazinon salivary concentrations not only can be used to predict the plasma levels of diazinon in rats, but also reflect the unbound fraction of diazinon in plasma.     

Biological monitoring of diazinon exposure using saliva in an animal model

Alternative biological monitoring methods are currently being pursued to better quantify pesticide exposures. In this study, the feasibility of using saliva as a tool for measuring diazinon exposure was determined in an animal model. Male Spraque-Dawley rats were dosed with 1 or 10 mg/kg diazinon by bolus intravenous injection. Time-matched saliva and arterial blood samples were collected from 10 to 250 min post administration. Diazinon was distributed and eliminated rapidly in rats following intravenous (iv) bolus injection, according to a two-compartmental pharmacokinetic analysis. Salivary concentration of diazinon showed a strong correlation with plasma concentration of diazinon. The saliva/plasma (S/P) concentration ratio of diazinon was not affected by administered dose, sampling time, or salivary flow rate, suggesting that salivary excretion of diazinon in rats is fairly constant. Diazinon concentrations in saliva were consistently lower than those in arterial plasma. The mean S/P concentration ratios of diazinon were 0.16 and 0.13 for 1 and 10 mg/kg iv bolus doses, respectively. It is most likely that the incomplete transfer of diazinon from plasma to saliva is due to protein binding of diazinon in plasma. If the protein-unbound fraction of diazinon in plasma is used to calculate the S/P ratio, the S/P concentration ratio of diazinon is close to unity. The results from this study support the conclusion that diazinon salivary concentrations not only can be used to predict the plasma levels of diazinon in rats, but also reflect the unbound fraction of diazinon in plasma.     

Effect of perfused rat mandibular-gland pHI on the ratio of procainamide concentration in saliva to that in venous effluent

The saliva to venous-effluent concentration ratio (S/E ratio) for procainamide (PA) was determined and compared with the ratio calculated by using the intracellular pH value of glandular cells. Exposed mandibular gland was perfused in situ with Krebs-Ringer bicarbonate buffer containing PA (10-100 micrograms/ml) and acetylcholine (ACh, 0.1 to 10 microM) or pilocarpine (10 microM). These perfusion conditions maintained almost normal physiological function of the mandibular gland throughout the perfusion period of 60 min, since the salivary Na+ and K+ concentrations were kept at almost constant levels, comparable with those reported in vivo, and the salivary flow, pH and protein level were also stabilized. Under fixed stimulation conditions with 1 microM ACh or 10 microM pilocarpine, the perfusate PA concentration ranging from 20 to 100 micrograms/ml did not affect the S/E ratio (approximately 0.3). There was a negative correlation between the S/E ratio and salivary pH when stimulated with 0.1 to 10 microM ACh. However, Matin's equation [S. B. Matin et al., Clin. Pharmac. Ther. 16, 1052 (1974)] employing venous effluent and salivary pH values did not explain fully these observed ratios. In contrast, Borzelleca's model [J. F. Borzelleca and J. W. Putney, J. Pharmac. exp. Ther. 174, 527 (1970)] for salivary drug transport using intracellular pH of the mandibular gland cells predicted S/E ratios relatively close to the observed values when the gland was perfused at pH 7.4 or 8.0.     

Prophylactic Effects Of Pilocarpine Hydrochloride On Xerostomia Models Induced By X-Ray Irradiation In Rats

1. In the present study, we investigated the prophylactic effects of pilocarpine hydrochloride on xerostomia models induced by either single (15 Gy) or repeated (8.6 Gy x3 days) X-ray irradiation in rats. Pilocarpine hydrochloride was administered orally 90 min before each irradiation session. Then, 7 days later, salivary volume, amylase activity and protein concentration in the saliva secreted from the right parotid gland were measured before and after a subsequent administration of pilocarpine hydrochloride (intraduodenal). 2. In irradiated no-pretreatment rats, irradiation induced a significant reduction in both spontaneous and pilocarpine hydrochloride-stimulated secretion (both total salivary volume and flow rate), regardless of the protocol used for X-ray exposure. In irradiated, pilocarpine hydrochloride-pretreated rats, salivary secretion was increased after stimulation by pilocarpine hydrochloride (intraduodenal) to a degree that depended on the pretreatment dose of pilocarpine hydrochloride (p.o.) in both xerostomia models. 3. There were no differences in amylase or protein concentrations between irradiated rats pretreated with pilocarpine hydrochloride and irradiated no-pretreatment control rats. 4. A decrease in the weight of the parotid gland was observed in rats exposed to either the single dose or repeated irradiation protocols. Changes in the submandibular gland were less marked than those in the parotid gland. These changes in gland weight were not affected by pilocarpine hydrochloride pretreatment. 5. The responsiveness of the parotid gland to subsequent stimulation with pilocarpine hydrochloride was apparently preserved in both xerostomia models by pretreatment with pilocarpine hydrochloride, which itself increased salivary secretion. This suggests that pilocarpine hydrochloride may exert functional protective effects against xerostomia that occurs following irradiation therapy through a stimulation of salivary secretion.     

A study on the distribution of T-3262 (tosufloxacin tosilate) in salivary glands of rats using microautoradiography

The distribution of T-3262 (tosufloxacin tosilate) in salivary glands of rats was investigated with frozen-microautoradiography. One and 4 hours after oral administration of 14C-T-3262 at 100 mg/kg to rats submandibular glands, parotid glands and sublingual glands were removed, and a microautoradiogram of each was made. In the submandibular gland and the parotid gland 14C-T-3262 was distributed at high levels throughout the glands taken at 1 and 4 hours after administration, but lower levels than the other glands were found in the sublingual gland at 1 hour. The results of this study suggested that T-3262 penetrates effectively into the saliva, because 14C-T-3262 is distributed well into glandular acinus, striated duct and excretory duct. The microautoradiography was a useful and reliable method for investigating the distribution of antimicrobial agents in salivary glands.     

Pharmacokinetics of cefotiam in plasma, parotid saliva and mixed saliva in healthy adults

Cefotiam (Spizef; CAS 61622-34-2) at a dose of 2 g was administered intravenously to 10 young, healthy, male volunteers. Multiple simultaneous blood, parotid saliva, and mixed saliva samples were collected for 7 h. The antibiotic assay was carried out by high-pressure liquid chromatography. Significant salivary cefotiam concentrations were found for 2 to 4 h, potentially inhibitory to a wide array of pathogens commonly isolated from the upper aerodigestive tract. Salivary cefotiam concentrations were correlated to plasma levels (p less than 0.01), but saliva/plasma ratios varied considerably. It is unlikely that passive diffusion is the applicable transfer mechanism for cefotiam secretion into saliva.     

Correlations of parotid saliva and blood ethanol concentrations

This paper is devoted to the detection and quantitation of blood and parotid saliva ethanol in both human subjects and rats. The human ethanol saliva-plasma ratio has been determined to be 1.04 utilizing a collection technique which is non-invasive and easily performed. The rat ethanol saliva-plasma ratio has been found to be 1.21 with a direct cannulation technique of the parotid duct. Differences between the human and rat ratios have been attributed to the method of salivary gland stimulation. The human parotid gland was stimulated by a reflex action of an organe-flavored lozenge, whereas the rat parotid gland was stimulated by a direct infusion of pilocarpine. The results indicate that the rat parotid secretion of ethanol is very similar to the human secretions, and the rat could possibly be utilized as an animal model for future alcohol salivary studies.     

Correlations of parotid saliva and plasma lidocaine concentrations in rats.

The concentration ratios of parotid saliva to plasma lidocaine were determined in rats after a single dose (10 mg of lidocaine/kg) and constant infusion (60 micrograms of lidocaine/kg/min). Parotid saliva and plasma samples were obtained at 10, 20, and 30 min after single-dose lidocaine administration and at 70, 80, and 90 min after the initiation of a lidocaine infusion. The saliva/plasma concentration ratios for lidocaine after single-dose administration decreased from 1.13 +/- 0.03 at 10 min to 0.51 +/- 0.06 at 30 min, whereas the ratios determined during the lidocaine infusion remained constant (0.43 +/- 0.03, 0.45 +/- 0.03, and 0.43 +/- 0.04) over the time period tested. The variable saliva/plasma concentration ratios obtained after single-dose administration may be associated with rapid drug distribution between the plasma and peripheral compartments and variation in lidocaine binding to plasma proteins. However, during constant lidocaine infusion, a steady-state concentration was achieved within 70 min, as demonstrated by the constant saliva/plasma concentration ratios.     

SALIVARY CONCENTRATIONS OF ATRAZINE REFLECT FREE ATRAZINE PLASMA LEVELS IN RATS

The protein binding of atrazine in plasma and its effect on salivary excretion of atrazine was determined in male Sprague-Dawley rats. The degree of protein binding of atrazine was determined at 3 steady-state plasma concentrations, 50, 150, and 250 mug/L, using an ultrafiltration technique. In total, 48 arterial blood samples were collected from 18 rats; 38 of 48 blood samples had their time-matched whole saliva samples. The average protein binding of atrazine ranged from 18% to 37% ; however, it was not significantly different across the 3 steady-state plasma concentrations nor among the individual rats. Overall, 26% of atrazine was bound to plasma proteins and not available for transport from blood into saliva. Protein binding of atrazine in plasma was not correlated with total atrazine plasma concentration nor with free atrazine plasma concentration, which indicates that the protein-bound fraction of atrazine is independent of plasma concentration within the range measured in this study (30-400 mug/ L). The average saliva/ plasma (S/P) concentration ratio of atrazine increased from 0.7 using total atrazine plasma concentration to 0.94 (S/fP) when free atrazine plasma concentrations calculated as 26% of protein binding was used. Salivary concentration was highly correlated with free atrazine plasma concentration. The results suggest that salivary concentration of atrazine not only reflects its total plasma level but accurately measures the portion of atrazine (free atrazine) in plasma, which may be of toxicological significance.     

Can saliva replace plasma for the monitoring of methadone?

The aims of this study were to determine the relationship between saliva and plasma methadone concentrations and the influence of variability in saliva pH. Saliva and plasma samples were taken before the daily dose of methadone in 60 patients undergoing methadone maintenance treatment (MMT). Saliva pH was measured immediately after sampling, and concentrations of (RS)-, (R)-, and (S)-methadone in saliva and plasma were assayed by LC/MS. In addition, unbound (R)- and (S)-methadone concentrations were measured in plasma samples by ultrafiltration. Plasma binding and pH differences between plasma and saliva were then used to estimate methadone saliva/plasma ratios and to compare them with observed values. Saliva pH ranged from 5.1 to 7.6 (mean +/- SD, 6.7 +/- 0.5). Plasma and saliva concentrations correlated weakly [(RS)-, r = 0.14, P = 0.007, n = 44; (R)-, r = 0.10, P = 0.04, n = 43; (S)-, r = 0.22, P = 0.002, n = 43], and the mean saliva-to-plasma methadone concentration ratios were 1.1 (+/-1.3 SD), 1.5 (+/-1.5), and 0.8 (+/-0.8), for (RS)-, (R)-, and (S)-methadone, respectively. Corresponding values based on unbound concentrations of methadone in plasma were 21 (+/-20.6, n = 31), 21 (+/-19, n = 34), and 17 (+/-15, n = 36). The salivary concentration-to-dose ratios showed statistically significant but weak inverse correlations with saliva pH [(RS)-, r = 0.27, P < 0.001; (R)-, r = 0.25, P < 0.001; (S)-, r = 0.29, P < 0.001, respectively]. There were significant correlations between predicted and observed saliva/plasma ratios [(RS)-, r = 0.44, P < 0.001, n = 31; (R)-, r = 0.58, P < 0.001, n = 32; (S)-, r = 0.10, P = 0.04, n = 34], but the mean predicted saliva concentrations were about 5 times lower than the mean observed values. The poor correlations between salivary and plasma methadone concentrations observed in this study are partly related to the effect of variable saliva pH. However, saliva pH explained only 10%-36% of the total variation. As a conclusion, monitoring methadone concentrations in saliva may not be a useful alternative to plasma concentration measurements. Correction for saliva pH measured immediately after collection improves the relationship between saliva and plasma methadone concentration, but most of the variation remains unexplained.     

Effects of cyclosporine a on the functions of submandibular and parotid glands of rats

• 1.1. The present study was designed to investigate the possible effects of long-term (45 days) administration of therapeutic doses of cyclosporine A (25 mg/kg/day), on the functions of submandibular and parotid glands of rats. Pure submandibular and parotid saliva were collected intraorally by microcannulation of the ducts.
• 2.2. The weight gains of the treated animals during the study and the weights of the salivary glands at the end of 45 days were reduced significantly as compared with those of controls.
• 3.3. Sialochemistry studies revealed a marked decrease in total protein concentration in saliva obtained from submandibular glands (P<0.05).
• 4.4. Determination of electrolyte concentrations in saliva of submandibular gland and serum showed considerable differences between treated and control groups.
• 5.5. Significant elevation of amylase activity in serum and parotid saliva was observed in the treated rats in comparison with controls (P<0.001).
• 6.6. Data presented here indicates that long-term administration of therapeutic doses of cyclosporine A causes significant alterations in salivary output and composition.

     

Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay.

1 Concentrations of phenytoin in mixed, parotid and submandibular saliva and serum were determined in normal subjects after an oral dose, using a specific double antibody radioimmunoassay which requires only 20 micronl fluid. 2 Semi-log concentration-time plots of phenytoin concentration in mixed saliva and serum gave good parallelism after the initial 14 h post-administration period. 3 The mean ratio of the mixed saliva: serum phenytoin concentration was 10.3% +/- 1.5 (s.d.) in seven normal subjects. 4 Phenytoin concentrations found in separate parotid and submandibular salivary fractions did not differ but were significantly greater (P less than 0.001) than those found in mixed saliva. 5 Phenytoin concentrations in all salivary fractions were independent of the volume of fluid produced and the degree of stimulation. 6 The rate of phenytoin secretion in the parotid and submandibular fluid was proportional to the salivary flow rate. 7 These data suggest that mixed saliva may be a suitable medium for the monitoring of phenytoin concentrations and may provide a non-invasive alternative to the direct determination of phenytoin in serum.     

Salivary CA130 with and without unilateral autonomic parotid denervation of rats fed different diets

BACKGROUND: Tumor markers such as CA130 can be determined in human whole saliva. Saliva represents an attractive body fluid for longitudinal studies. MATERIALS AND METHODS: CA130 was determined in parotid saliva from 8 rats fed different diets, with or without autonomic denervation. RESULTS: CA130 could be determined in parotid saliva of rats, irrespective of diet and/or autonomic denervation. Whether the numerical decrease in CA130 observed after autonomic denervation is statistically significant requires further work. CONCLUSIONS: Since salivary CA130 has been shown to decrease following treatment with anti-cancer drugs in humans, the ability to determine this tumor marker in rat saliva opens new opportunities for optimizing cancer chronotherapy in the experimental laboratory.     

Bromocriptine concentration in saliva and plasma after long-term treatment of patients with Parkinson's disease

Summary Salivary and plasma concentrations of bromocriptine (BCT), a dopamine agonist, were measured by gas chromatography in four patients with Parkinson's disease. All the patients had been on mono-therapy with BCT for years, and during the 3 weeks prior to the investigation they received constant but individually different dosage regimens. Paired samples of pure, parotid, serous saliva and of blood were collected hourly during one eight hour dose interval. The concentrations of BCT in saliva were very low and there was a ten-fold range in the areas under the salivary and plasma concentration/time curves. It is concluded that in clinical practice measurement of BCT in saliva is not suitable for exact estimation of the plasma concentration of BCT. Using the measured salivary pH and the plasma BCT concentration, calculations based on the Henderson-Hasselbalch equation showed that the assumption of about 99% plasma protein binding of BCT best fited the observed concentrations of BCT in saliva.     

Lowered susceptibility of muscarinic receptor involved in salivary secretion of streptozotocin-induced diabetic rats.

We investigated the responses of salivary secretion and the susceptibility of the muscarinic receptors in the salivary glands of the streptozotocin (STZ)-induced diabetic rats (STZ rats). Giving water ad libitum, the amount of whole saliva with no stimulation was similar in the STZ and the control rats. Pilocarpine increased salivary secretion in both groups, although the effect in the STZ rats was two to three fold less than in the control rats. If the animals were restricted from taking water for 6 h, salivary secretion was not slightly changed in the STZ rats in spite of a remarkable increase in the control. An obvious decrease in salivary secretion of the STZ rats was negatively correlated with an increase in urination. Furthermore, salivary secretion from the parotid gland was increased in a dose-dependent manner with pilocarpine in the control rats, but not in the STZ rats. In the [3H]quinuclidinyl benzilate (QNB) binding studies for muscarinic receptor of the STZ rats, Bmax was decreased in the parotid gland and Kd was increased in the submandibular gland. Competitive inhibition of [3H]QNB binding to both glands showed an increase in IC50 of pilocarpine and carbachol. These results suggest that a decrease in salivary secretion of STZ rats is not only induced by a water loss, but also closely associated with the lowered susceptibility of the muscarinic receptors.