Allopurinol rectal absorption in the rabbit

Allopurinol is used clinically, with apparent success, as a rectal suppository for patients unable to take the medication by mouth. However, plasma levels of the drug or its active metabolite, oxipurinol, following administration of such dosage forms in man are either very low or undetectable. The absorption of allopurinol from rectal dosage forms was evaluated using the rabbit as a model. Following administration of the drug in suppositories formulated with cocoa butter, cocoa butter with 2% Tween 80 or polyethylene glycol, no measurable levels of either allopurinol or oxipurinol were seen. consistent with results reported in man. Administration of a rectal solution produced erratic absorption at a level less than 10% of that seen orally. The results indicate that allopurinol is not absorbed rectally and that there is no rationale for administering the drug by the rectal route. Continued clinical use of allopurinol suppositories should be documented by controlled efficacy studies.     

Rectal versus oral absorption of codeine phosphate in man

Rectal absorption of codeine phosphate from various dosage forms was studied in man. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. The plasma concentrations of codeine were measured by means of HPLC analysis after a single dose of 60 mg codeine phosphate in a cross-over study in 7 volunteers. Compared with oral dosing rectal absorption from an aqueous solution or a fatty suppository produced an almost identical plasma concentration profile with similar interindividual variations. Comparing the absorption rate characteristics it appeared that rectal absorption from an alkaline solution containing codeine phosphate proceeded significantly (P < 0·05) more rapid than after oral dosing. No essential difference in bioavailability was observed between the various rectal and oral dosage forms.     

Plasma concentrations following single doses of morphine sulfate in oral solution and rectal suppository

Plasma concentrations of morphine and morphine-3-glucuronide (morphine's major metabolite) were determined following single 10-mg doses of morphine sulfate in oral solution and rectal suppository. Ten patients with pain secondary to cancer were given a single 10-mg dose of oral morphine sulfate in an oral solution or rectal suppository on sequential days. Blood samples were collected at time zero and periodically for 4.5 hours after administration. Plasma concentrations of morphine and morphine-3-glucuronide were determined using liquid chromatography with electrochemical detection. Higher mean concentrations of morphine were achieved with the rectal suppository than with the oral solution at all time points, and the overall mean plasma morphine concentration for the entire 4.5-hour period was significantly higher for the rectal suppository than for the oral solution. There were no significant differences between dosage forms in mean morphine-3-glucuronide concentrations at individual time points or over the entire period. A single dose of morphine sulfate in a rectal suppository was better absorbed than in an oral solution. Further studies are needed to compare the clinical efficacy of these dosage forms under steady-state conditions.     

Bioavailability of nifedipine suppository in healthy subjects

Nifedipine rectal suppositories were prepared with polyethylene glycol as a base as a treatment for hypertensive emergency. The suppository which contained 10 mg of nifedipine had adequate physical characteristics and nifedipine stability for practical use. Bioavailability of the suppository was compared to that of an oral capsule (10 mg of nifedipine content) in healthy subjects. The mean nifedipine plasma concentration curve following rectal administration showed slightly delayed absorption as compared to the oral administration. However, there was no significant difference in the AUC from 0 to 7 h between the suppository and the capsule, which suggested the same extent of bioavailability for both dosage forms. A hypotensive effect of the nifedipine suppository for the subjects was observed 30 min after the administration and the effect was more definite and more prolonged compared to the oral capsule.     

Rectal bioavailability of lidocaine from a suppository and a slow release preparation in man

In a previous investigation it was shown that the systemic availability of lidocaine in humans following rectal administration of an aqueous solution was about twofold higher than after oral administration. Most likely this was due to a partial avoidance of hepatic ‘first-pass’ metabolism. In the present study the systemic availability of two different rectal dosage forms of lidocaine was examined. Six healthy volunteers received in a balanced cross-over design a rectal capsule with slow release granules and a suppository, both containing 300 mg lidocaine as lidocaine. HCl. Plasma concentrations were measured for 8 h after drug administration by capillary gas chromatography. The mean rectal systemic availability of the two preparations was not significantly different: 49% (suppository) and 54% (capsule), when compared to the results obtained in a previous investigation after intraveneous administration. Early defaecation occasionally caused a loss of still unabsorbed drug. Mean bioavailability of the rectal aqueous solution was 70%. As expected, the absorption from the suppository was more rapid than from the capsule: the mean peak times were 122 min and 195 min respectively (p < 0.05). The mean maximum plasma concentrations were comparable: 0.70Μg/ml (suppository) and 0.69Μg/ml (capsule) respectively. These results confirm the previous findings that rectal administration of lidocaine results in a higher systemic availability than oral administration, but they are at the same time rather variable with the dosage forms studied.     

4种直肠给药剂型对家兔的局部药效学研究

目的:分析4种直肠给药剂型在直肠中的分布特点。方法:以亚甲蓝为指示剂,制备浓度均为0.5%的栓剂、灌肠液、凝胶剂和泡沫剂,将12只家兔分为4组,将4种制剂分别经直肠给药,2h后解剖,观察家兔直肠染色部分的长度、染色的深度、黏膜皱襞是否染色及制剂在体内保留时间等指标。结果:4种剂型中,泡沫剂组着色部分最长,平均达(28.3±1.3)cm(P<0.05),且颜色最深;栓剂组着色部分最短,平均为(12.5±0.8)cm,且颜色最浅,但制剂保留时间较长。凝胶剂组与灌肠液组着色长度和保留时间介于上述2种剂型之间。结论:泡沫剂在治疗直肠结肠疾病给药方面具有显著优势,值得深入研究。     

Clinical assessment of theophylline absorption from Theolair-SR and two other sustained-release formulations relative to a conventional formulation

In this single dose study with 8 subjects, the rate and extent of theophylline absorption from 3 sustained-release formulations (Theolair-SR tablet, Slo-phyllin Gyrocaps, and an experimental SR tablet) were compared to absorption from a conventional formulation (Theolair tablet) that has been shown to provide both prompt and complete absorption. Plasma theophylline level versus time profiles show that the rate of absorption from all 3 sustained-release formulations is slower than from the conventional tablet. In addition, the higher plasma levels at later times and the slower apparent plasma elimination rate of theophylline following the Theolair-SR tablet as compared to the conventional Theolair tablet indicate that drug absorption continues over a more prolonged period of time. Plasma AUC data indicate, with good assurance, that the extent of theophylline absorption is essentially complete from all 3 sustained-release formulations when compared to data for the conventional tablet. Statistical analyses with plasma AUC data indicate that the Theolair-SR tablet should provide both reliable and complete drug absorption. Projected plasma drug levels for multiple dosage regimens (simulated on the basis of the single dose data from this study) demonstrate that, even with a twice daily dosage regimen, the Theolair-SR tablet has acceptable sustained-release characteristics relative to the conventional Theolair tablet with 4 daily doses, and that the sustained-release properties compare favorably with those of Slo-phyllin Gyrocaps.     

Rectal absorption of metronidazol from polyethylene glycol suppositories

The rectal absorption of metronidazol from an aqueous suspension, a fatty suppository and three different polyethylene glycol suppositories was studied in healthy volunteers and compared with absorption from an oral solution. Rectal absorption was found to be rather slow for all suppositories. Of all rectal dosage forms, the polyethylene glycol suppositories gave the highest peak plasma levels and the highest relative bioavailability. Compared with oral administration, a relative bioavailability of 80% could be obtained.     

The rabbit as an experimental model for biopharmaceutical studies following rectal administration of theophylline

In order to find a suitable animal model for biopharmaceutical studies after rectal application of theophylline, the pharmacokinetics of theophylline following the administration in rabbits of three different rectal preparations were examined and compared with those of the oral and i. v. route. No significant formulation related impact from the studied rectal dosage forms on the bioavailability of the drug was found. However, the unexpected rapid achievement of peak serum concentration after insertion of the suppository lacked any correlation with human experiments. It was concluded that the evaluation of rectal theophylline medication for man cannot directly be based on the data obtained from rabbits.     

Colonic spread of three rectally administered mesalazine (Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy

Background : Rectal administration of enemas, foams and suppositories is the most efficient method of delivering locally-acting drugs to the distal colon, sigmoid colon and rectum. Healthy volunteers provide an effective population to compare different formulations for rectal drug delivery. However, there is still only limited comparative information available on the dispersion of such dosage forms in human subjects. Therefore, the objective of this scintigraphic study was to compare colonic spread of an enema, a rectal foam and a suppository formulation in healthy volunteers.
Methods : This was a randomized, crossover study in eight healthy male volunteers. Each received Pentasa rectal formulations as either a 100 mL suspension enema (1 g mesalazine), one actuation of a non-CFC propellant rectal foam (1 g mesalazine in 5 mL concentrate, expanding to 40 mL on actuation), or one suppository (1 g mesalazine) on three separate occasions. The spread of the radiolabelled formulations was assessed over a 4-h period by gamma scintigraphy.
Results : The formulations were retained by all subjects for the whole of the 4-h imaging period. The enema spread to the splenic flexure in 7 out of 8 subjects, but was retained in the rectum and sigmoid colon in one individual. The foam spread as far as the descending colon in four subjects. In the remaining individuals the foam was retained in the rectum and sigmoid colon. The spread of the suppository was limited and confined to the rectum.
Conclusions : The findings of this study are consistent with previous research and support the intended clinical uses of the enema, foam and suppository formulations to treat distal ulcerative colitis, proctosigmoiditis and proctitis, respectively. The results highlight the potential of gamma scintigraphy in providing in vivo `proof of concept' data to help verify the targeting of pharmaceutical products to their intended site of delivery.     

Apparent absorption kinetics of micronized griseofulvin after its oral administration on single- and multiple-dose regimens to rats as a corn oil-in-water emulsion and aqueous suspension.

This investigation was designed to quantitate and compare in the rat the oral absorption characteristics of micronized griseofulvin from a corn oil-in-water emulsion dosage form containing suspended drug and a control aqueous suspension after single-dose (50 mg/kg) and multiple-dose (50 mg/kg every 12 hr for five doses) administrations. The time course of intact drug in the plasma of all animals was best described by a one-compartment open model with apparent zero-order absorption. In contrast to that observed with the aqueous suspension, the onset of drug absorption after single-dose administration of the corn oil emulsion was significantly delayed. This difference disappeared upon multiple dosing of the two dosage forms, with the mean onset being quite rapid in both cases. Administration of a single dose of the antibiotic as the corn oil emulsion resulted in considerable increases in the maximum plasma levels of griseofulvin and in the duration, relative extent, and uniformity of drug absorption compared to those observed after administration of the control aqueous suspension. The potentiating effects of the lipid on drug absorption persisted on multiple dosing but at a somewhat reduced level.     

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.     

Biopharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal,oral, intramuscular and intravenous administration in man

Rectal absorption of diazepam was studied in man and compared with intravenous, intramuscular and oral administration. Plasma concentrations of diazeparn were measured by means of HPLC analysis after a single dose of 10 mg diazeparn in a cross-over study in 9 healthy volunteers.Plasma concentration—time curves following intravenous administration were described by a tri-exponential function consistent with a three-compartment model system. It was calculated that the drug will not exhibit measurable first pass metabolism.Comparing the absorption rate constants it appeared that rectal absorption of a solution of diazeparn proceeded significantly (I <0.05) more rapidly than absorption after oral and intramuscular administration. Absorption from a macrogol suppository dosage form was rather slow.The mechanism of the rapid rectal absorption of diazeparn from the solute state was discussed. No essential difference in bioavailability was observed between the intramuscular injection, rectal solution and tablets as compared with the intravenous injection. Only for the suppository dosage form was bioavailability calculated to be significantly lower.     

Rectal infusion of the model drug antipyrine with an osmotic delivery system

An osmotically-powered rectal drug delivery system, was used for the rectal infusion of the model drug antipyrine. The system, which is slightly larger than a normal suppository, has a nominal pumping rate of 43 μl h^{? 1} over at least 30 h. Four healthy volunteers kept two such systems in their rectum for a sum total of 98 h. Saliva and plasma concentrations were determined at regular intervals and in all cases a very constant steady-state saliva and plasma concentration was reached and maintained. Defecation and reinsertion of the drug delivery system did not cause any irregularities in the concentration profile. The system was very well tolerated by the volunteers.     

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.     

直肠给药新制剂的研究进展

直肠内黏膜血管丰富,有利于药物在全身的循环,并能部分避免首过效应导致的肝代谢.直肠给药制剂具有快速吸收,无痛等优点,有时可作为静脉给药的替代和补充.本文比较了常用直肠给药栓剂、灌肠液、凝胶剂和泡沫剂的优缺点,以期为临床用药提供参考.     

Comparative pharmacokinetic analysis of theophylline in serum and saliva

The kinetics of theophylline disposition in serum and saliva was evaluated after single and multiple circadian administration of a sustained-release theophylline formulation (Euphyllin CR) to 20 asthmatic children. Salivary concentrations were proportional to serum drug levels, with the significant correlation of r = 0.92. The kinetics of theophylline absorption and elimination and the mean residence time were identical in both saliva and serum estimations. In steady-state conditions after multiple drug administration, the area under the concentration-time curve and the magnitude of peak levels in saliva were reduced proportionally with decreased serum theophylline concentrations. The significantly higher volume of theophylline distribution in saliva confirmed that salivary concentrations represent the free, pharmacologically active fraction in plasma. The determination of theophylline salivary levels could therefore be of clinical importance. The values of the saliva/serum ratio determined in the elimination phase of concentration-time curves for individual patients were constant and stable over the treatment period of three weeks. Saliva appears to be a convenient and noninvasive alternative to blood for the assessment of the variable pharmacokinetic parameters of theophylline and for around-the-clock monitoring of individual dosage regimens, especially in paediatric patients.     

Antipyretic therapy

Summary The absorption of paracetamol from syrup, tablet and two different suppository bases was compared in six adult volunteers using urinary excretion measurements. The total amount of paracetamol and its metabolites excreted and the peak excretion rates were lower from the suppository bases than from the oral dosage forms. Absorption was a little better from a polyethylene glycol suppository base than from a triglyceride base. The antipyretic efficacy of a paracetamol syrup and suppository at a dose of 10 mg/kg was compared in 30 children between the age of 4 months and 12 years, who had infections and a rectal temperature above 38.5°C. Both dosage forms produced a significant decrease in temperature, the greatest fall being about 2 hours earlier with the oral dosage form. The syrup also seemed to be significantly (p<0.05) more effective (maximum fall of temperature 1.58°C) in reducing fever than the suppository, which produced its greatest fall of temperature (1.24°C) six hours after insertion of the suppository. From the practical point of view both forms can be regarded as safe and effective antipyretics.     

Biopharmaceutics of rectal administration of drugs in man

Rectal absorption of acetylsalicylic acid and its calcium salt was studied in man and compared with oral absorption. Plasma concentrations of acetylsalicylic acid and salicylic acid were measured by means ofHplc analysis, after a single dose of acetylsalicylic acid (500 mg) and after single rectal doses of acetylsalicylic acid (500 mg) and calcium acetylsalicylate (640 mg) in a cross-over study in 8 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration rectal absorption of acetylsalicylic acid can be equally rapid, if the volume and the pH of the aqueous micro-enema was optimized (20 ml, pH 4.0). Rectal absorption of calcium acetylsalicylate occurred very slowly. If fatty suppositories were used smaller particles favoured the rate of acetylsalicylic acid absorption. Compared with oral administration absorption from the optimized suppository dosage form proceeded significantly (P < 0.05) slower. For all rectal dosage forms, the extent to which acetylsalicylic acid reached the general circulation intact, was smaller than after oral administration. In honour of ProfessorPolderman on the occasion of his retirement.     

Absorption rate and bioavailability of valproic acid and its sodium salt from rectal dosage forms

Summary Rectal and oral absorption of valproic acid and its sodium salt by man were compared to explore the possibility of rectal administration of the drug. The plasma concentration of valproic acid was measured by gas chromatography after a single oral dose of sodium valproate 600 mg, and after single rectal doses of sodium valproate 600 mg and valproic acid 520 mg, in a cross-over study in 7 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration, rectal absorption of sodium valproate from an aqueous micro-enema was fast and complete. The free acid was absorbed more rapidly from fatty suppositories than was the sodium salt. The absorption rate from the rectum increased with the dose of valproic acid. Both findings are consistent with a diffusion — absorption mechanism based on the pH-partition hypothesis. Differences in the chemical composition of the fatty suppository base were not reflected in differences in absorption rate and relative bioavailability. No essential difference in absorption rate was observed if volunteers remained lying or sitting during the experiment. Rectal dosing with valproic acid 520 mg dissolved in 4 ml suppositories, twice a day resulted in steady-state plasma concentrations of 50 to 100 µg · ml^–1, within the therapeutic range.Data have been presented in: F. Moolenaar, Ph. D. Thesis, Groningen, The Netherlands