Determination of saliva: total plasma chloroquine levels relationship by high performance liquid chromatography

The use of saliva chloroquine concentrations measurement as a noninvasive technique in the evaluation of the pharmacokinetics of the drug was investigated. Chloroquine concentrations in saliva and plasma were measured in eight healthy volunteers after a single oral dose of two tablets of chloroquine sulfate. The saliva: total plasma concentrations (S/P) ratio was found to be approximately constant in the absorption (0.4 +/- 0.07), distribution (0.47 +/- 0.08), and elimination (0.46 +/- 0.05) phases. Thus, saliva sampling for chloroquine concentrations was found to be a useful noninvasive technique for the estimation of all the pharmacokinetic parameters of the drug and hence, for chloroquine pharmacokinetic studies.     

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.     

唾液和血浆中10-羟基卡马西平的药动学及其浓度的相关性研究

目的:考察唾液与血浆中10-羟基卡马西平的药动学及其浓度的相关性。方法:20名志愿者禁食1晚后,服用奥卡西平600mg,在96h内同步收集血液和静息唾液样本,用已建立的高效液相色谱方法对10-羟基卡马西平进行分析。结果:唾液和血浆中10-羟基卡马西平的AUC_(0～∞)分别为(162±s 86)和(186±27)mg·h·L~(-1)。c_(m(?))分别为(8．1±1．4)和(7．2±1．3)mg·L~(-1),t_(max)分别为(4．7±2．7)和(5．4±1．5)h,t_(1/2)为(11．1±2．5)和(10．2±1．7)h,MRT_(0～(相似文献   

Comparison of plasma and saliva levels of diazepam.

1. Salivary, unbound and total plasma levels of diazepam have been compared in nineteen subjects. 2. Salivary diazepam levels were significantly higher (P < 0.001) than, but closely related to the corresponding unbound levels (r = 0.97) at 2.5-3 h after administration of the drug. 3. The results presented suggest that saliva levels can be used to predict the corresponding plasma levels at a given time, but there is no 1:1 relation between the unbound diazepam concentration in plasma and the saliva level of the drug.     

Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only.     

Comparison of plasma and saliva levels of metoprolol and oxprenolol

1 Plasma and saliva levels of metoprolol and oxprenolol have been compared in two groups of healthy volunteers. 2 Mean salivary oxprenolol levels were lower than, but closely related to the corresponding plasma levels (r=0.93), the mean ratio of saliva:plasma concentration being 0.42. 3 Mean salivary metoprolol concentrations were considerably greater thatn the corresponding plasma levels and the relationship between the concentrations in the two fluids was less clear. 4 The evidence presented suggests that oxprenolol diffuses passively whilst metoprolol is actively secreted into saliva. The mechanism involved in the active process is not known.     

Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.     

Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping

AIMS

To compare midazolam kinetics between plasma and saliva and to find out whether saliva is suitable for CYP3A phenotyping.

METHODS

This was a two way cross-over study in eight subjects treated with 2 mg midazolam IV or 7.5 mg orally under basal conditions and after CYP3A induction with rifampicin.

RESULTS

Under basal conditions and IV administration, midazolam and 1′-hydroxymidazolam (plasma, saliva), 4-hydroxymidazolam and 1′-hydroxymidazolam-glucuronide (plasma) were detectable. After rifampicin, the AUC of midazolam [mean differences plasma 53.7 (95% CI 4.6, 102.9) and saliva 0.83 (95% CI 0.52, 1.14) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean difference plasma 11.8 (95% CI 7.9, 15.7) ng ml⁻¹ h] had decreased significantly. There was a significant correlation between the midazolam concentrations in plasma and saliva (basal conditions: r = 0.864, P < 0.0001; after rifampicin: r = 0.842, P < 0.0001). After oral administration and basal conditions, midazolam, 1′-hydroxymidazolam and 4-hydroxymidazolam were detectable in plasma and saliva. After treatment with rifampicin, the AUC of midazolam [mean difference plasma 104.5 (95% CI 74.1, 134.9) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean differences plasma 51.9 (95% CI 34.8, 69.1) and saliva 2.3 (95% CI 1.9, 2.7) ng ml⁻¹ h] had decreased significantly. The parameters separating best between basal conditions and post-rifampicin were: (1′-hydroxymidazolam + 1′-hydroxymidazolam-glucuronide)/midazolam at 20–30 min (plasma) and the AUC of midazolam (saliva) after IV, and the AUC of midazolam (plasma) and of 1′-hydroxymidazolam (plasma and saliva) after oral administration.

CONCLUSIONS

Saliva appears to be a suitable matrix for non-invasive CYP3A phenotyping using midazolam as a probe drug, but sensitive analytical methods are required.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Midazolam is a frequently used probe drug for CYP3A phenotyping in plasma. Midazolam and its hydroxy-metabolites can be detected in saliva.

WHAT THIS STUDY ADDS

• The concentrations of midazolam and its hydroxy-metabolites are much lower in saliva than in plasma, but the midazolam concentrations in both matrices show a significant linear correlation.
• Saliva appears to be a suitable matrix for CYP3A phenotyping with midazolam, but very sensitive methods are required due to the low concentrations of midazolam and its hydroxy-metabolites.

     

Time-dependent variability of chloroquine secretion into human saliva

Chloroquine has been reported to be secreted into human saliva. This is a report of a study designed to underscore the importance of the finding. It involved the administration of 600 mg chloroquine per oral to seven volunteers and 150 my by intramuscular route to six others. Blood and simultaneous saliva samples were collected and analyzed for the drug by an HPLC method. The results showed that chloroquine reaches peak concentration at the same time in both plasma and saliva after oral administration of the drug. A good correlation was obtained between the AUC values derived from saliva and plasma level data. Saliva to plasma concentration ratios obtained after administration of the drug by both routes were high (mean>11) and exhibited a time-dependerit variability. These results suggest that an active process, among other mechanisms, may be invobred in the transter of chloroquine into human saliva. Caution should be exercised in the use of salva for therapetic monitoring of chloroquine.This study was supported by Obajemi Awolowo University Research, grant 1427 BRC.O. Onyeji, F.A. Ogunbond. Time-dependent variability of chloroquine secretion into human saliva.     

Pharmacokinetics of diethylcarbamazine: prediction by concentration in saliva

The concentration of diethylcarbamazine in saliva was used to determine pharmacokinetic parameters, in comparison to plasma and urine concentrations. Six healthy adult male volunteers were administered 150 mg diethylcarbamazine with 400 ml of water. At seven different time intervals, blood, urine and saliva samples were taken, and different pharmacokinetic parameters measured. The plasma-saliva concentration ratio was calculated as 1.53 whereas the observed ratio was 3.82. The half lives, times to reach peak plasma concentration, and elimination rate constants did not show any significant difference in the different samples. The plasma peak concentration and areas under the curve were significantly (p<0.05) increased from those of the saliva. At 24 h, when diethylcarbamazine was absent in urine, the plasma and saliva concentrations were almost zero. Diethylcarbamazine is secreted in saliva, and its concentration in saliva can be used to monitor drug therapy.     

Pharmacokinetics and plasma steady state levels of doxycycline in undernutrition.

1 The kinetics of doxycycline were studied in well nourished and undernourished male subjects. 2 The area under the curve after an intravenous dose was reduced and total body clearance was significantly elevated with a shorter/beta-phase half life of the drug in undernourished subjects. 3 The percentage of total drug excreted in urine in 48 h and renal clearance of the drug were similar in both groups. 4 Plasma protein binding was significantly reduced and gamma-glutamyltransferase levels tended to be higher in the undernourished as compared to normals. 5 Increased total body clearance of the drug appeared therefore to be due to higher metabolism of drug in undernourished subjects. This increased metabolism is probably due to lower protein binding of the drug and/or induction of drug metabolism. 6 Plasma Cmin concentrations of doxycycline determined at steady state were lower in undernourished subjects. However, they were within the therapeutic range. 7 The observed alterations in kinetics of doxycycline therefore do not warrant a change in dosage regimen in undernourished subjects.     

罗通定在唾液和皿浆中浓度的测定及相关性分析

目的建立大鼠唾液和血浆中罗通定浓度的HPLC测定方法,研究单次静脉注射后大鼠唾液及血浆中罗通定浓度的相关性。方法色谱柱为Diamonsil（R）C18柱（250mm×4．6mm,5μm）;流动相为甲醇：水（70：30,V/V）;流速1．0mL·min^-1;柱温30℃;检测波长281nm。测定唾液和血浆中的罗通定浓度,并对腮腺、颌下腺唾液浓度与对应血浆质量浓度进行Pemarson相关分析。结果罗通定的唾液和血浆浓度在0．1-20．0mg·L^-1和0．5．40．0mg·L^-1内线性关系良好,在唾液和血浆中的最低定量限和相对回收率分别为0．1mR·L^-1、100．97％-107．50％和0．5mg·L^-1、98．30％～111．20％,日内、日间精密度（RSD）均〈10％;静注给药后,腮腺和颌下腺唾液浓度与对应血浆浓度呈正相关,Pearson相关系数（R）分别为0．9,37（P〈0．01）和0．985（P〈0．01）。结论首次建立了同时适用于唾液和血浆中微量罗通定分析的HPLC方法;唾液和血浆中的罗通定浓度具有良好的相关性,在罗通定的药动学研究及临床药物浓度监测时可以考虑以唾液代替血浆样本进行分析,     

Desipramine plasma levels and clinical response: evidence for a curvilinear relationship

Twenty-six outpatients with major depression completed a 6-week, fixed dose trial of desipramine and provided plasma samples. Recovery after 6 weeks, defined in either of two ways, corresponded to lower desipramine levels, while clinical status at 4 weeks bore no apparent relationship to plasma levels. Upper limits of 140 or 155 ng/ml emerged depending on the outcome measure used. Patients with endogenous depression, those with primary depression, and those with abnormal dexamethasone suppression test results yielded similar therapeutic thresholds, while the sharpest blood level/response relationship emerged in the subgroup with an abnormal escape from dexamethasone.     

Effects of Hange-koboku-to (Banxia-houpo-tang) on neuropeptide levels in human plasma and saliva

Hange-koboku-to (Banxia-houpo-tang), a Chinese herbal (Kampo) medicine, has been used for improvement of hoarse voice, something foreign body sensation in the throat and/or esophagus, and swallowing reflex, among other conditions. One of the mechanisms of the empirical effects is assumed to be due to local changes in neuropeptide levels locally. We investigated the effects of Hange-koboku-to on neuropeptides, calcitonin gene-related peptide (CGRP), substance P, somatostatin, and vasoactive intestinal peptide (VIP) in plasma and saliva, as well as on salivary secretion in healthy subjects. A single oral administration of Hange-koboku-to caused significant increases in substance P-immunoreactive substance (IS) (40 min) in plasma, and slightly increased in CGRP-IS and somatostatin-IS in plasma compared with placebo. In saliva neuropeptides, Hange-koboku-to caused significant increases in substance P-IS (20 min) and somatostatin-IS (40, 60 min), and a slight increase in VIP-IS. However, a single Hange-koboku-to stimulation did not have a significant effect of sialosis volume. These results seem to suggest that Hange-koboku-to improves hoarse voice, something foreign body sensation in the throat and esophagus, and swallowing reflex disorder, by stimulation of neuropeptidergic nerves locally.     

Pharmacokinetics of pentoxifylline: Blood and saliva distribution dynamics in healthy volunteers

Plasma and saliva pentoxifylline concentrations were measured by HPLC in nine volunteers aged from 19 to 32 years given Trental at a dose of 200 mg on an empty stomach. Plasma and saliva pentoxifylline concentrations were determined, along with pharmacokinetic parameters. There was a strong linear correlation (r = 0.9308) between mean blood and saliva pentoxifylline concentrations. There were no significant differences in blood and saliva pentoxifylline concentrations at any time point or in pharmacokinetic parameters calculated from plasma and saliva distributions. The results obtained here show that saliva samples can be used instead of blood for studies of the pharmacokinetics of pentoxifylline. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 1, pp. 3–5, January, 2008.     

Hubble-bubble (water pipe) smoking: levels of nicotine and cotinine in plasma,saliva and urine

OBJECTIVES: The purpose of the present study was to assess the levels of nicotine and cotinine in biological fluids (plasma, saliva, and urine) following hubble-bubble (HB) smoking. METHODS: Fourteen healthy male volunteers, aged 28 +/- 8 years, body weight of 82.7 +/- 13.53 kg, participated in the study. All volunteers were habitual HB smokers for 3.29 +/- 1.90 years who smoked at least 3 runs per week with an average of 20 g Mua'sel per run. Volunteers were requested to avoid smoking, at least 84 hours prior to the time of the study. After baseline samples were taken, volunteers started smoking 20 g of Mua'sel for a period of 45 minutes. Heparinized blood samples (5 or 10 ml each) were drawn for nicotine and cotinine analysis before, during and after the smoking period. Saliva samples were collected just before smoking (time 0) and at the end of smoking (45 min). Urine also was collected at time 0 and 24-hour urine collection was also taken to measure nicotine and cotinine excretion. Nicotine and cotinine were extracted from samples and assayed by gas chromatography. All data are presented as mean +/- SEM throughout the text, Tables and Figures unless indicated otherwise. RESULTS: Plasma nicotine levels rose from 1.11 +/- 0.62 ng/ml at baseline to a maximum of 60.31 +/- 7.58 ng/ml (p < 0.001) at the end of smoking (45 min). Plasma cotinine levels increased from 0.79 +/- 0.79 ng/ml at baseline to its highest concentration of 51.95 +/- 13.58 ng/ml (p < 0.001) 3 hours following the end of smoking. Saliva nicotine levels significantly rose from 1.05 +/- 0.72 to 624.74 +/- 149.3 ng/ml and also saliva cotinine levels significantly increased from 0.79 +/- 0.79 ng/ml to 283.49 +/- 75.04 ng/ml. Mean amounts of nicotine and cotinine excreted in urine during the 24-hour urine collection following smoking were equal to 73.59 +/- 18.28 and 249 +/- 54.78 microg, respectively. CONCLUSION: Following a single run of HB smoking, plasma, saliva and urinary nicotine and cotinine concentration increased to high values. This observation suggests that HB may not be an innocent habit, as people believe.