The influence of food on the bioavailability of a slow release theophylline preparation

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.     

Pharmacokinetics and bioavailability of theophylline following enema and suppository administration in man

The pharmacokinetics and bioavailability of theophylline from a commercial oral elixir of theophylline, a rectal suppository of aminophylline, and a rectal enema of theophylline monoethanolamine was compared in six normal subjects. Using a complete crossover design, the fasted subjects received a single dose of each dosage form. Blood and saliva samples were collected at frequent time intervals for 24 h, and the plasma assayed for theophylline by a specific thin-layer chromatography densitometric method. No statistically significant differences existed among the three dosage forms with respect to Cmax and AUC corrected for the elimination rate constant and the dose (mg kg-1). However, tmax was significantly larger for the suppository. While the rate of absorption was significantly slower for the suppository, no differences in the extent of absorption existed among the three dosage forms. A one-compartment open model with apparent first-order absorption adequately described the plasma concentration-time data for the elixir and enema, whereas the suppository data were best fitted by a one-compartment open model with apparent zero-order absorption and a lag time. A rate-limiting, concentration-independent release of drug from the base most likely accounts for the slow absorption of theophylline from the suppository. While the saliva:plasma ratio remained fairly constant for most of the study period, the large variability found during the absorption phase following drug administration limits the usefulness of this parameter as a monitor of theophylline plasma concentrations.     

Comparative bioavailability of 5-aminosalicylic acid from a controlled release preparation and an azo-bond preparation

Background: Knowledge of the bioavailability of 5-aminosalicylic acid (5-ASA, mesalazine) from the different 5-ASA-containing drugs is important for rational therapy of inflammatory bowel diseases. Methods: The local and systemic bioavailability of 5-ASA from a controlled release 5-ASA preparation (Pentasa—2, 4 or 6 g/day) was investigated and compared with the azo-bond 5-ASA preparation olsalazine (Dipenturn— 2 g/day) in 13 healthy volunteers during steady state conditions. Results: The therapeutically relevant parameter of 5-ASA at the rectal level, expressed as the mean concentration in faecal water, showed a significant trend towards higher concentrations with increasing Pentasa dose: 9.2 mmol/L, 19.0 mmol/L and 24.4 mmol/L, respectively. The concentration of olsalazine 2 g/day was 16.0 mmol/L. The concentration of the metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA) did not rise with increasing Pentasa dose, indicating saturable presystemic acetylating capacity of 5-ASA. Total urinary excretion of 5-ASA and Ac-5-ASA, as a percentage of the daily ingested 5-ASA dose, remained constant on the three Pentasa doses, but there was a significant increase in the 5-ASA fraction. Mean steady state plasma concentrations of 5-ASA and Ac-5-ASA were significantly higher on Pentasa 4 g/day and 6 g/day than on 2 g/day. Values on Pentasa 2 g/day were comparable with those on olsalazine 2 g/day. Conclusions: The study confirmed that 5-ASA is released from Pentasa in a predictable manner, the amount released increasing with dose. Olsalazine is an excellent generator of 5-ASA in the colon.     

Rectal bioavailability of lidocaine in the dog: evaluation of first-pass elimination

The disposition of lidocaine was studied in beagle dogs after I.V., P.O. and rectal administration. Lidocaine HCl solution was used for the I.V. and P.O. studies. For rectal administration 3 gels were prepared: 1) lidocaine base in a hydrophilic vehicle, 2) lidocaine HCl in a hydrophilic vehicle, and 3) lidocaine base in a lipophilic vehicle. The gels were administered 3 cm deep in the rectum. Additionally, the gel of lidocaine HCl in a hydrophilic vehicle was also administered 10 cm deep in the rectum. No significant differences between I.V. and all extravascular administrations were observed for terminal half-life, total clearance and apparent volume of distribution. The systemic bioavailability after P.O. was 31%, and between 32% and 53% for the rectal dosage forms. The lidocaine base in lipophilic vehicle had the lowest systemic availability, the lowest peak concentration and the longest time to peak, whereas the lidocaine HCl in a hydrophilic vehicle, inserted 10 cm deep into the rectum, had the highest systemic bioavailability, highest peak concentration and shortest time to peak. The dog seems to be an excellent model for evaluation of peroral and rectal first-pass elimination.     

Relative bioavailability of a paracetamol suppository

Summary The relative bioavailability of a new paracetamol suppository (Panodil) and tablets in doses of 0.5 and 1 g was investigated in eight healthy subjects. The tablets were absorbed faster and higher peak plasma concentrations were obtained than after the suppositories. The bioavailability of the suppositories was approximately 80% of that of the tablets at both dose levels. There was no indication of capacity-limited elimination at either the two doses investigated.     

Pharmacokinetic profile of a novel slow release preparation of molsidomine

Summary A novel slow release preparation containing 24 mg molsidomine has been investigated in 6 healthy subjects. Individual concentration/time-profiles after the tablet showed two separate concentration peaks at 2.2 h and 15.0 h. The relative bioavailability of the slow release preparation in comparison to an aqueous solution of molsidomine was 0.67. The in vivo dissolution profile revealed either a progressive decrease in dissolution velocity caused by altered physico-chemical conditions in the ileum and the colon or a progressive reduction in the absorption constant. In all subjects deconvolution revealed a punctual increase in absorption about 15 h post-dose, coinciding with the second peak of the concentration/time-profile. Therapeutic plasma levels of molsidomine (> 5 ng · ml⁻¹ were not maintained over 24 h by this slow release formulation.     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

Comparative bioavailability of a sustained release preparation of amitriptyline and conventional tablets

Summary A sustained release preparation of amitriptyline has been compared with conventional tablets in eight healthy human volunteers. The tablet produced a distinct peak in serum concentration shortly after administration, whereas the sustained release preparation caused a slow rise to a plateau. The maximum serum concentration and the time of its occurrence differed significantly between the two preparations. The differences between the serum concentration curves of the two preparations can be explained on the basis of a two compartment model of amitriptyline pharmacokinetics and from a difference in the absorption rate. The similar clinical effect obtained with a lower daily dose of the sustained release preparation than of the tablet cannot be accounted for in terms of pharmacokinetics. It is possible that a single evening dose of sustained release amitriptyline gives a more appropriate serum concentration profile of amitriptyline and its active metabolite nortriptyline than a conventional tablet taken three times a day.     

Medicament release from fatty suppository bases

The consistency in terms of viscosity index and the rheology of mixtures of cacao butter with different fats was examined with a Stormer viscometer. Most bases showed shear rate thickening at low stresses and marked fall in consistency between 35°–40°. The drug release from them was related inversely to the consistency of the bases.     

Comparative bioavailability of a morphine suppository given rectally and in a colostomy

Summary In eight patients with a colostomy, plasma morphine levels were followed for 8 h after administration of 20 mg morphine chloride as a suppository, first rectally and after at least 48 h via the colostomy. The bioavailability after administration in the colostomy showed very great variation; the mean value compared to rectal bioavailability was only 43% (range 0.1-127%). In four patients the plasma concentrations of morphine after colostomy administration were lower at all times than after rectal administration, and in three only small amounts of morphine were detectable. One patient showed higher plasma concentrations after colostomy application than after rectal administration. It is concluded that administration of morphine suppositories in a colostomy cannot be recommended.     

环孢素A栓剂的相对生物利用度

目的 :研究环孢素A栓剂与环孢素A口服液的相对生物利用度。方法 :利用荧光偏振免疫分析仪测定家兔直肠给予环孢素A栓剂 2 5mg·kg-1(n =4)与口服环孢素A口服液 2 5mg·kg-1(n =4)后血药浓度 ,计算两者的药物动力学参数和相对生物利用度 ,并进行统计学分析。结果 :环孢素A栓剂的相对生物利用度为 ( 12 2 .4± 2 9.3) % ,两者的动力学参数间差异无显著性 (P >0 .0 5 )。结论 :环孢素A栓剂与环孢素A口服液具有生物等效性 ,可以通过对环孢素A栓剂的进一步改进 ,提高其生物利用度。     

Comparison of the bioavailability of two slow release preparations of disopyramide

Summary The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L. A. 250 mg b. d. and Dirytmin Durettes 300 mg b. d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period.With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L. A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L. A.     

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers

Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml^–1) was significantly lower than after the tablets (74.3 ng · ml^–1). The AUCs following the two treatments did not differ significantly from each other.The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).     

The bioavailability and pharmacokinetics of slow release nifedipine during chronic dosing in volunteers.

Eight healthy volunteers received slow release nifedipine 20 mg 12 hourly, for six doses. A nifedipine pharmacokinetic profile was performed after the fifth dosing interval using 12 sampling times over 12 h. A specific high pressure liquid chromatography (h.p.l.c.) nifedipine assay was used. Six of the volunteers subsequently received an i.v. infusion of 3.5 mg of nifedipine after an identical period (five dosing intervals) of chronic oral dosing with slow release nifedipine 20 mg 12 hourly. An identical pharmacokinetic profile was performed after the infusion. Bioavailability, clearance (CL), apparent volume of distribution (V), apparent half life (t1/2) and area under the curve (AUC) were calculated. The geometric mean apparent t1/2 for the slow release preparation was 6.3 +/- 2.0 h. In the six volunteers, the mean bioavailability was 46% (range 29-86%), the mean CL was 588.0 +/- 67.1 ml min-1, the mean apparent V was 160.1 +/- 61.7 l. The pharmacokinetics of slow release nifedipine during chronic dosing appear similar to those derived from single dose studies.     

Naproxen suppository: Tissue response and comparative bioavailability

Summary The absorption of naproxen from Witepsol and Carbowax suppository bases was found to compare closely to that from an equivalent oral dose. Although the drug was readily absorbed from both rectal formulations, naproxen in Witepsol base produced a more rapid rise of plasma levels. — No significant local tissue irritation occurred following a course of six suppositories as determined by anoscopy and rectal biopsy. — No objective or subjective side effects were noted.     

对乙酰氨基酚栓剂人体相对生物利用度和生物等效性

目的:研究进口试验制剂与国产对乙酰氨基酚栓剂(参比制剂)的相对生物利用度和生物等效性.方法:采用HPLC法测定18例健康男性志愿者单次交叉直肠给予参比制剂2粒(300mg)及试验制剂2粒(250mg)后的血药浓度,经CRFB软件处理,计算其药动学参数和相对生物利用度,评价两制剂的生物等效性.结果:试验制剂和参比制剂的t1/2分别为(3.94±1.54)和(3.81±1.24)h;Tmax分别为(1.56±0.57)和(1.58±0.43)h;平均滞留时间MRT0～tn分别为(5.67±1.44)和(5.40±1.28)h;Cmax分别为(1.73±0.38)和(1.61±0.34)μg·mL-1;AUC0～tn分别为(8.01±2.20)和(7.54±1.82)μg·h·mL-1.试验品与参比品的相对生物利用度为(109.07±27.92)%,经统计学处理,试验品AUC0～t的90%置信区间为97.20%～115.85%,Cmax的90%置信区间为98.64%～116.97%.结论:两制剂生物等效.     

利多卡因缓释胶丸皮下植入的药代动力学

目的：研究利多卡因缓释胶丸（ＬＳＲＰ）在兔和大鼠体内的药代动力学。方法：运用高效液相色谱法（ＨＰＬＣ）测定ＬＳＲＰ在血浆和组织中的浓度。结果：发现兔皮下植入ＬＳＲＰ（２０，４０，８０ｍｇ·ｋｇ－１）后，血浆药物浓度—时间曲线符合缓释制剂的一室开放模型。３种剂量的ＬＳＲＰ吸收半衰期Ｔａ１／２均较利多卡因注射液（ＬＴ，１０ｍｇ·ｋｇ－１，ｓｃ）明显延长。３种剂量ＬＳＲＰ的峰浓度（Ｃｍａｘ）分别为０．２４±０．０９，１．２５±０．２３，５．６５±０．１０ｍｇ·Ｌ－１，而ＬＩ（１０ｍｇ·ｋｇ－１，ＳＣ）的Ｃｍａｘ为２．１８±０．３２ｍｇ·Ｌ－１。４０ｍｇ·ｋｇ－１ＬＳＲＰ经大鼠皮下植入后，在局部皮下组织中利多卡因浓度明显高于血浆、脑、心、肝和肾组织中浓度，并在给药后４８ｈ仍能维持在１．１８μｇ·ｇ－１水平。结论：ＬＳＲＰ经皮下植入后的缓释效果明显。提示ＬＳＲＰ能延长利多卡因的局麻、镇痛作用，并可能减轻其全身毒性。     

Inclusion complex effect on the bioavailability of clotrimazole from poloxamer-based solid suppository

To study the effect of β-cyclodextrin (βCD) inclusion complex on the bioavailability of clotrimazole from poloxamer-based suppository, formulations composed of P 188, propylene glycol and different molar ratio of clotrimazole-βCD inclusion complex were prepared. Clotrimazole (1%) has been formulated in a suppository using the thermo sensitive polymer P188 (70%) together with propylene glycol (30%). To increase its aqueous solubility, clotrimazole was incorporated as its inclusion complex at various molar ratios with βCD (1:0.25, 1:0.5, 1:1, and 1:2). The inclusion complex was characterized by differential scanning calorimetry (DSC), XRD and phase solubility studies. It was observed that the complexation with βCD, particularly at high molar ratio (F3 (1:1) and F4 (1:2)) decreased the release profile of clotrimazole considerably. However, suppositories containing inclusion complex at low molar ratio (F1 (1:0.25) and F2 (1:0.5)) showed excellent release profile compared to control formulation. In vivo study in rats at 15 mg/Kg dose showed that the F1 and F2 (82.39 ± 15.40 and 67.05 ± 8.79, respectively) significantly increased the AUC compared to that of F3 (41.48 ± 11.51), F4 (23.34 ± 8.37) and control (46.7 ± 7.87) suppositories. Thus, the suppositories containing inclusion complexes prepared at low drug to βCD molar ratio (F1) could be a potential suppository formulation to increase the bioavailability of hydrophobic drugs such as clotrimazole.     

Development of a thermo-reversible insulin liquid suppository with bioavailability enhancement.

The purpose of this work is to develop a thermo-reversible insulin liquid suppository, which undergoes a phase transition to bioadhesive gels at body temperature and enhances the bioavailability of insulin. The effects of insulin and sodium salicylate on the physicochemical properties of a liquid suppository composed of poloxamer P 407, P 188 and polycarbophil were investigated. The pharmacodynamic study and quantitative histological assessment of the rectal mucosa of rats were carried out after the dose of insulin-loaded liquid suppositories with different amounts of sodium salicylate into streptozotocin-treated rats. Only thermo-reversible insulin liquid suppository [insulin/P407/P188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)] showed the optimal physicochemical properties and good safety in rats. It gave significantly lower plasma glucose levels, AUC(0-->4h) (the area below basal glucose level) and C(nadir) (the plasma glucose levels at the nadir) than did the solid and liquid suppositories without sodium salicylate in rats, indicating that the insulin from liquid suppository with sodium salicylate could be well absorbed in rats due to the absorption enhancing effect of sodium salicylate. It is concluded that thermo-reversible insulin liquid suppository [insulin/P 407/P 188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)], which was easy to administer without any pain during insertion and remained at the administered sites, could have a potential to be developed as a more convenient, safe and effective rectal delivery system of insulin.