Pharmacokinetic aspects of the sublingual administration of vincamine

The sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.     

Plasma timolol levels after oral and intravenous administration

Summary The plasma kinetics of timolol administered orally and intravenously to 5 male subjects were examined. Bioavailability was reduced by 25% when the drug was taken orally. Mean plasma half-life after oral dosing was 4.86 h, and after intravenous administration it was 4.56 h; the difference was not significant. The volume of distribution was 3.5 l/k. It is suggested that timolol is little affected by the first pass effect, even though there is marked interindividual variation in availability and peak plasma level.     

舌下给药研究进展

目的：综述舌下给药的研究进展。方法：查阅近年来国内外相关文献，进行分析、整理、归纳及总结。结果：舌下给药具有吸收迅速、避免首关效应、生物利用度高、方便安全，能随时停止给药等优点。但目前专门用于舌下给药的制剂还不普遍，并且在给药剂量、药物的吸收、剂型等方面存在不足。结论：舌下给药制剂在临床各种病症中都得到了应用，并且在某些疾病的治疗上发挥着不可替代的作用。     

Pharmacokinetics of the new analgesic,meptazinol, after oral and intravenous administration to volunteers

Summary The pharmacokinetics of meptazinol (Meptid^®) have been studied in nine male volunteers after single and multiple oral administration of 200 mg tablets and also after a single 25 mg intravenous dose. Plasma concentrations of meptazinol were determined by HPLC using fluorescence detection. Drug absorption after oral dosage was rapid, peak plasma concentrations being reached between 0.25 and 2 h after drug administration. Subsequent elimination proceeded in an apparently mono-exponential fashion with a half-life of 2 h, although after intravenous dosage there was evidence of an initial rapid distributive phase. The mean total plasma clearance was 2.21/min and the mean apparent volume of distribution (Vd) was 4.99 l/min. The bioavailability ranged from 1.9 to 18.5% (mean=8.7%) and was related to the rate of absorption. Multiple dosing, 6-hourly for 3 days, did not produce any accumulation above that predicted from a single dose. Plasma protein binding of the drug was 27.1% and did not vary over the therapeutic concentration range of 25 to 250 ng/ml.     

Enhanced bioavailability of triazolam following sublingual versus oral administration

The rate and extent of the absorption of triazolam following sublingual and oral administration were evaluated in this study. Eight healthy volunteers received triazolam 0.5 mg in a commercially available tablet, by sublingual and oral routes on two occasions in random sequence. Plasma triazolam concentrations during 24 hours after each dose were measured by electron-capture gas-liquid chromatography. The mean total area under the curve for sublingual administration was significantly larger than that following oral dosage (28.9 vs 22.6 ng-hr/mL, P less than .025). The peak plasma concentration after sublingual dosage was also higher than after oral administration (4.7 vs 3.9 ng/mL, P less than .1). No significant differences between sublingual and oral administration were found for the elimination half-life of triazolam (4.1 vs 3.7 hr) and the time of peak concentration (1.22 vs 1.25 hr) after dose. Thus, the bioavailability of triazolam after sublingual administration is increased by an average of 28% compared with oral administration of the same dose, possibly because first-pass extraction is bypassed. Clinical effects of triazolam may likewise be enhanced by sublingual dosage.     

Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses

The pharmacokinetic profiles of a sublingual and a conventional oral lorazepam tablet formulation were established following chronic administration to twelve healthy male volunteers. Fitting a multi-dose equation based on a one-compartment model to the observed data, the average elimination half-lives for the sublingual and oral doses are estimated to be 11 and 8 h, respectively, while the corresponding absorption half-lives are 15 and 55 min; this confirms earlier reports that the sublingual formulation is more rapidly absorbed. The observed time to steady-state for both formulations was approximately 3 days, which agrees well with that predicted from previous single dosing studies. Although the sublingual formulation yields a higher average steady-state minimum plasma concentration than the oral formulation (41.6 versus 38.1 ng ml-1), the maximum lorazepam concentration achieved during steady state was approximately 83 ng ml-1 for both formulations. The average steady-state plasma concentration is estimated to be 63 ng ml-1, independent of the formulation used.     

A general model of metabolite kinetics following intravenous and oral administration of the parent drug

A model of metabolite pharmacokinetics is developed in terms of residence time distributions and derived non-compartmental measures. It provides quantitative insight into factors determining the concentration-time curve of metabolite following intravenous and oral administration of the precursor drug. The AUCs and higher curve moments (mean residence times and relative dispersions) are calculated/predicted and their dependence on mean absorption time, fraction of first-pass metabolism and intrinsic disposition residence times of the parent drug and metabolite, respectively, is discussed. An AUC-based method for the determination of the first-pass effect is proposed which is not influenced by drug absorption. The approach is valid for linear pharmacokinetic systems exhibiting hepatic and renal elimination of the precursor drug; it is not restricted to specific compartmental models. Limitations of previous concepts of metabolite kinetics are defined. Criteria are presented for the appearance of concave metabolite curves in a semi-logarithmic scale.     

盐酸苯海拉明乳膏的制备及质量控制

目的：制备盐酸苯海拉明乳膏,并建立质量控制方法。方法：用水包油型基质制备本品,以高效液相色谱法测定盐酸苯海拉明的含量,并建立相关质控指标。结果：盐酸苯海拉明线性范围为0．1—3．2μg,线性关系良好（r=0．9999）,平均回收率为97．83％,RSD为0．84％。结论：处方及制备工艺合理可行。质量标准可靠、全面,可用于本品的质量控制。     

Human dolasetron pharmacokinetics: I. Disposition following single-dose intravenous administration to normal male subjects.

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0.6 to 5 mg kg-1, dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2-4 h. Less than 1 per cent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0.625 h (median). Its median terminal disposition half-life was 7.56 h; median values for fraction of dose excreted in urine and renal clearance were 31.0 per cent and 2.68 ml min-1 kg-1, respectively. Over the dose-range covered, pharmacokinetics of both dolasetron and reduced metabolite appeared to be independent of dose. The median ratio of the areas under the plasma concentration-time curves for metabolite relative to dolasetron was 11.9. As a result of its activity and significant plasma concentrations, reduced dolasetron may play a significant role in pharmacodynamic activity.     

Pharmacokinetics of dolasetron following single- and multiple-dose intravenous administration to normal male subjects

Dolasetron, Anzemet^TM, a 5-hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto-reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg^?1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg^?1 d^?1 on days 2–9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half-life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20–4.43 mL min^?1 kg^?1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single-dose pharmacokinetics of this metabolite.     

Characterization of Hydrochloride and Tannate Salts of Diphenhydramine

Proper characterization is an important aspect of any dosage form design. The objective of this work was to characterize tannate salt and hydrochloride salt of diphenhydramine. As a part of characterization studies, Differential scanning calorimetry was used to investigate thermal effects and nature of salts, supported by X-ray powder diffraction. Scanning electron microphotographs was used to surface topography of salts of diphenhydramine. Fourier-transform infrared spectroscopy, solubility study and flowability studies were carried out as part of characterization. Differential scanning calorimetry and X-ray powder diffraction studies indicated amorphous nature of the tannate while hydrochloride salt has crystalline properties. Scanning electron microphotographs indicated the differences in surface topography between both the salts. Solubility studies at different pH showed pH dependant solubility of both the salts and less solubility of tannate. Stability of bulk drug at accelerated conditions of 40^°/75% RH was determined for both salts. Good stability of both salts was observed.     

盐酸苯海拉明凝胶的制备及质量控制

目的:制备盐酸苯海拉明凝胶并建立其质量控制方法。方法:以羧甲基纤维素钠等作为凝胶基质,以正交试验筛选基质最佳配方,并采用紫外分光光度法在258nm波长处测定盐酸苯海拉明的含量。结果:制备的凝胶均匀细腻,分散性好;盐酸苯海拉明检测浓度在100～400μg/ml范围内线性关系良好(r=0.9999,n=6),平均回收率为99.95%,RSD=0.95%(n=9)。结论:该制剂质量稳定,质控方法可靠。     

The pharmacokinetics of diclofenac sodium following intravenous and oral administration

Summary The pharmacokinetics of diclofenac were examined following single rapid intravenous injection and also following single oral doses to healthy female volunteers. After intravenous injection plasma levels of diclofenac fell rapidly and were below the limits of detection at 5.5 h postdosing. Individual drug profiles were described by a triexponential function and mean half-lives of the three exponential phases were 0.05, 0.26 and 1.1 h. After oral doses of enteric-coated tablets, the lag time between dosing and the appearance of drug in plasma varied between 1.0 and 4.5 h. However once drug absorption had commenced similar plasma drug profiles were obtained in different individuals. Peak plasma diclofenac levels ranged from 1.4 to 3.0 µg · ml^–1. The mean terminal drug half-life in plasma was 1.8 h after oral doses. This value was not significantly greater than the value of 1.1 h following intravenous doses. Fifty percent of orally dosed diclofenac did not reach the systemic circulation due, predominantly, to first-pass metabolism.     

Disposition of butanal oxime in rat following oral,intravenous and dermal administration

1. The disposition of [1-¹⁴C]butanal oxime (BOX) was determined in the rat after oral, i.v. and dermal administration. 2. Oral doses of [¹⁴C]BOX (2 and 20?mg/kg) were predominantly excreted in the urine (> 42%) and converted to ¹⁴CO₂ (> 30%) and about 10% of the dose remained in the tissues 72 h post-dosing. 3. Eight and 16% of a 2 and 20?mg/kg dermal dose of BOX, respectively, were absorbed, due in part to rapid volatilization from the surface of the skin. 4. Oral doses of BOX were transformed into several polar and/or anionic metabolites that include sulphate conjugates and a significant amount of thiocyanate. 5. The effect of inhibitors on the metabolism of BOX was investigated using 1- aminobenzotriazole (ABT; an inhibitor of diverse cytochrome P450s) and trans-1,2- dichloroethylene (DCE; an inhibitor of CYP2E1). No thiocyanate anion was detected in the urine of rat treated with DCE or ABT. ABT markedly increased the production of ¹⁴CO₂ and excretion as volatile metabolites. DCE had no effect on ¹⁴CO₂ excretion, but increased exhalation of radiolabel. ABT also effectively blocked the expression of toxic effects attributable to cyanide in rat given near-lethal doses of BOX. 6. The data are consistent with two distinct pathways of metabolism for BOX, (1) reduction to an imine, hydrolysis and subsequent conversion of butyraldehyde to ¹⁴CO₂ and (2) CYP3A-catalysed dehydration of BOX to butyronitrile followed by CYP2E1- catalysed release of cyanide.     

紫外分光光度法测定苯海拉明麻黄碱滴鼻液的含量

目的 建立苯海拉明麻黄碱滴鼻液中盐酸苯海拉明和盐酸麻黄碱的含量测定方法。方法 采用双波长分光光度法消除组分间干扰进行含量测定。结果 方法的线性关系良好。盐酸苯海拉明平均回收率为99．0％，RSD为1．29％；盐酸麻黄碱平均回收率为99．7％，RSD为1．32％。结论 本法简便、快速、准确，适宜于医院制剂分析。     

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.     

The effect of sublingual captopril versus intravenous enalaprilat on angiotensin II plasma levels

A 44-year-old woman, with a history of familial adenomatous polyposis, complicated by carcinoma of the colon, for which a proctocolectomy had been performed, now presented with metastasis located in the pancreas. Treatment consisted of chemotherapy followed by a partial pancreaticoduodenectomy. Due to ischemia, resection of the small intestines was performed the same day. After admission, a transesophageal echocardiography showed an ejection fraction of 40%. Because enteral administration of drugs was impossible, intravenous enalaprilat 2 mg once a day for 1 day followed by sublingual captopril 25 mg twice a day were started. Blood samples were taken before and after administration. After 1 day of sublingual captopril treatment the angiotensin II level decreased with more than 50%, comparable to the decrease seen after intravenous administration of enalaprilat. Sublingual captopril has been used in the treatment of hypertensive crisis and heart failure. Although frequently reported, no study has investigated the effect on angiotensin II levels after sublingual administration in heart failure patients. This case-report demonstrated that sublingual administration of 25 mg captopril twice a day yielded a considerable decrease in angiotensin II plasma levels which was comparable to the effect seen after an intravenous administration of 2 mg enalaprilat.