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.     

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.     

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.     

Rectal versus oral absorption of diflunisal in man

Rectal absorption of diflunisal from various dosage forms was studied in man. The rectal dosage forms included fatty and macrogol suppositories, an aqueous suspension and solutions with various solvents in order to achieve complete dissolution of diflunisal. A comparison was made with an orally administered suspension. The plasma concentrations of diflunisal were measured by means of HPLC analysis after a single dose of 250 mg diflunisal in a cross-over study in 7 volunteers.Compared with oral administration, rectal absorption conditions are limited as a consequence of the poor solubility characteristics of diflunisal. Therefore attempts were made to improve absorption conditions by varying the nature of the rectal dosage form. The addition of alkali and solvents such as polyethylene glycol and glycofurol, did result in an increase of the rate of absorption, whereas the bioavailability 8 h after administration did rise up to 80% as compared with oral dosing. In the case where suppositories are employed, a fatty vehicle rather than a water-soluble base should be chosen in order to stimulate the driving force for absorption. It is concluded that 500 mg diflunisal suspended in a 4 ml fatty mass results in peak plasma concentrations comparable with an oral dose of 250 mg diflunisal.     

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     

Biopharmaceutics of rectal administration of drugs in man 7. Absorption rate and bioavailability of phenobarbital and its sodium salt from rectal dosage forms

In this report it will be shown that rectal administration of phenobarbital and its sodium salt can be looked upon as an alternative route of administration.Plasma phenobarbital concentrations were measured in 6 volunteers after a single oral dose (219 mg) of sodium phenobarbital and after single rectal doses of phenobarbital (200 mg) or sodium phenobarbital (219 mg). In the case of the rectally administered aqueous dosage forms of phenobarbital no distinct difference in absorption rate occurred whether the sodium salt or the free acid was used. Rectal administration of both types of micro-enemas results in absorption which is less rapid than after oral administration of the sodium salt. However, the final and total absorption of phenobarbital and its sodium salt after 6.5 h is practically complete, compared with oral administration. The in vitro release of phenobarbital from fatty suppositories using a coarse powder (125–250 μm) of sodium phenobarbital and with a fine powder (<20 μm) of phenobarbital showed marked differences. The rectal absorption profile of the aqueous and fatty dosage forms of sodium phenobarbital in vivo was quite similar. A much slower absorption rate was observed if the free acid was used in the fatty suppository dosage form.     

Preliminary study on the absorption profile after rectal and oral administration of methadone in human volunteers

Methadone is a potent, long acting narcotic analgesic which can be orally administered due to its almost complete bioavailability. There is a growing interest in the rectal route of administration in the case of acute postoperative or chronic malignant pain. Since virtually no data were available on the rectal absorption profile of methadone in man, plasma concentrations of methadone were determined by means of HPLC analysis after a single dose of 10 mg methadone HCl in a cross-over pilot study in five volunteers. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. Compared with oral dosing, the extent of rectal absorption from an aqueous solution was almost 80% up to 8 h after dosing. Although the mean peak concentration and the AUC_0-8h was significantly lower (p < 0.01), no marked difference in t_max was observed: 2.8 and 3.1 h respectively. Rectal absorption conditions of methadone from fatty suppositories (3 ml) were found to be less favourable. The peak plasma concentration was only reached 3–4 h after administration, whereas the relative bioavailability up to 8 h after dosing ranged from 35–58%. This rate-limiting absorption pattern may be due to the critical solubility properties of methadone HCl at physiological pH.     

Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base

STUDY OBJECTIVE: To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base. DESIGN: Unblinded, single-dose, randomized, crossover trial. SETTING: University-affiliated pharmacokinetics and biopharmaceutics laboratory. SUBJECTS: Six healthy subjects. INTERVENTION: Subjects were given a single 200-mg dose of phenytoin as an oral suspension and a rectal suppository separated by a 1-week washout. MEASUREMENTS AND MAIN RESULTS: Blood for plasma phenytoin concentrations was obtained at baseline and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. Plasma was analyzed by high-performance liquid chromatography (coefficient of variation < 6%) for total phenytoin concentration. Phenytoin maximum concentration (Cmax), time to Cmax (Tmax), time to first measurable concentration (Tlag), and area under the curve from time zero to time of last measurable concentration (AUClast) were estimated for oral and rectal administration by WinNonlin (v 1.1) and compared using Wilcoxon's signed rank test (p<0.05 for statistical significance). Two subjects did not have detectable plasma phenytoin concentrations after rectal administration. For the other four subjects, median rectal Cmax was significantly lower than oral Cmax (0.4 vs 1.9 microg/ml, p=0.028), median rectal Tmax did not differ from oral Tmax (11.9 vs 8.0 hrs, p=0.465), and median rectal AUClast, although highly variable, was significantly lower than oral AUClast (5.4 vs 36.2 microg x hr/ml, p=0.046). No Tlag was seen after oral administration, but with rectal administration the median Tlag was 2 hours. The estimated relative bioavailability of rectal phenytoin suppositories based on AUC0-24 was 4.7%, with individual values ranging from 0-58.3%. CONCLUSION: It appears that absorption of phenytoin from polyethylene glycol rectal suppositories in healthy subjects is highly variable and unpredictable. Thus this formulation is not recommended.     

The relative bioavailability of metoprolol following oral and rectal administration to volunteers and patients

The pharmacokinetics, efficacy and safety of metoprolol tartrate 25 mg fatty suppositories were studied in 5 healthy volunteers and in 8 patients suffering from instable angina pectoris. Metoprolol 25 mg capsules were used as a control oral dosage form. Metoprolol showed a considerable rectal bioavailability (AUC, C max) and was absorbed quickly from the rectum (T max). In both groups rectal bioavailability was comparable. However, oral bioavailability was much lower in the volunteer group than in the patient group. Furthermore, ratios of metoprolol/aOHmetoprolol concentrations in plasma and urine gave an indication for a partial avoidance of the first pass effect after rectal administration. Further research is necessary to define an exact rectal dosage of metoprolol. In all patients, a substantial drop in heart rate, systolic and diastolic blood pressure was seen after administration of the first suppository. Metoprolol suppositories appear to be an effective, safe and suitable alternative for patients who are in need for beta blocking medication and who are unable to take oral medication for a certain amount of time.     

Bioavailability of acetaminophen suppositories.

Urinary excretion of acetaminophen after rectal administration of three suppository formatulations obtained from hospital and commercial sources was compared to that after oral administration of a tablet dosage form. The absorption of acetaminophen from the suppositories was extremely variable and showed relative bioavailabilities of 68.4 to 87.5% when compared to the oral absorption of the drug from the tablet. The rate of bioavailability differed markedly between products and, in one case, the suppository dose of acetaminophen was so slowly absorbed that the clinical effectiveness of the product is doubtful. The study points out the need for in vivo evaluation of hospital pharmacy manufactured products.     

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.     

Intravaginal Morphine: An Alternative Route of Administration

The availability of various dosage forms allows morphine to be administered in a number of ways. However, if the oral and rectal routes are not feasible, the parenteral one may appear to be the only viable option. Morphine was administered by the intravaginal route in a 44-year-old woman as an alternative to intravenous patient-controlled analgesia. The dosage forms included sustained- and immediate-release tablets as well as regular suppositories. The initial dosage was calculated according to guidelines for switching to oral administration and titrated to response. Adequate pain control was achieved, but due to unpredictable bioavailability, close monitoring was essential.     

Pharmacokinetic evaluation of ethionamide suppositories.

The absorption and elimination of ethionamide (ETA) after oral tablets and rectal suppositories were determined in 12 healthy, adult male volunteers. A randomized, double-blind, double-dummy, crossover design was used. Treatments compared 250-mg ETA tablets and a placebo suppository to a 500-mg ETA suppository and two placebo tablets, given 7 days apart. Blood samples were collected at predetermined intervals for 12 hours after the dose. Serum concentrations of ETA were determined using high-performance liquid chromatography. The area under the serum concentration-time curve was used to compare the relative bioavailability of ETA from the two preparations. Relative bioavailability after rectal administration was 57.3% of that after oral administration. The maximum serum concentration after rectal administration was 33% of that after oral administration. Higher doses of ETA and serum concentration monitoring are recommended whenever the suppositories are used.     

Enhancement of dissolution and absorption of mefenamic acid by egg albumin

The dissolution behavior and absorption of mefenamic acid following oral and rectal administration from drug:egg albumin solid dispersions have been studied in comparison with those of the drug alone. The interaction of drug with egg albumin in aqueous solution and solid state were examined by solubility analysis, dialysis experiments, and X-ray diffractometry. The results showed that the dissolution rate of mefenamic acid, and also the release of drug from witepsol H-15 suppositories, were significantly increased by using egg albumin:drug solid dispersions. Although egg albumin:drug solid dispersion enhanced the mean serum levels and the area under serum concentration-time curves after oral and rectal administration compared with those of the drug alone, no significant differences were found between the mean residence time values of drug and its solid dispersion. It was also noted that the extent of bioavailability of mefenamic acid and its solid dispersion following oral administration was significantly greater than that following rectal administration.     

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.     

Morphine hydrochloride suppositories. II. Bioavailability of morphine hydrochloride suppositories in dogs

Bioavailabilities of morphine after rectal administration of three different morphine.HCl suppositories were evaluated in dogs, whose rectum was lavaged or non-lavaged. The suppositories were prepared with three fatty bases (Witepsol H-15, Witepsol W-35, Suppocire AT) by the fusion method. The release of morphine from the suppositories was examined after stored for two weeks at 30 degrees C. The plasma concentrations of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were determined by high-performance liquid chromatography. The bioavailabilities of morphine after rectal administration were compared with those after intravenous and oral administration of morphine++.HCl solution. In the case of rectal lavaged dogs, the plasma levels of morphine after rectal administration of morphine.HCl solution were higher than those after oral administration of morphine.HCl solution. The release of morphine from Witepsol H-15 suppository was more rapid than those from other suppositories. Morphine after rectal administration of Witepsol H-15 suppository was rapidly absorbed in the rectum, and the inter-animal variation of its plasma levels was smaller than those of other suppositories. In rectal non-lavaged dogs, the bioavailabilities of morphine after rectal administration of morphine.HCl solution and suppositories decreased more than those of rectal lavaged dogs. Although the bioavailability of morphine after rectal administration of morphine.HCl was decreased by the influence of contents in the rectum, morphine from Witepsol H-15 suppository was more rapidly absorbed in the rectum, and the inter-animal variation of its plasma levels was smaller. These results indicate that, among their suppositories, Witepsol H-15 suppository is available for the terminal care of malignant disease.     

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.     

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.     

Biopharmaceutical investigation of rectal suppositories. Part 2(1): Pharmaceutical and biological availability of phenobarbital and phenobarbital-sodium

The influence of the suppository base and drug solubility on the release an absorption of phenobarbital and phenobarbital-sodium from model suppositories was investigated. It was established that the pharmaceutical and biological availability of phenobarbital is higher from a hydrophilic base because of its improved solubility. The rate and the degree of release of phenobarbital-sodium are more significant from lipophilic bases. The bioavailability of two drug forms-phenobarbital and phenobarbital-sodium--is almost equal after rectal and oral administration.     

Morphine hydrochloride suppositories. I. Bioavailability of morphine hydrochloride suppositories in rats

Bioavailabilities of morphine after rectal administration of three different morphine-HCl suppositories (5 mg/kg) were evaluated in rats. The suppositories were prepared with three fatty bases (Witepsol H-15, Witepsol W-35, Suppocire AT) by the fusion method. The plasma and brain concentrations of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were determined by high-performance liquid chromatography. The bioavailabilities of morphine after rectal administration were compared with those after intravenous and oral administration of morphine.HCl solution (5 mg/kg). The plasma levels of morphine after rectal administration of morphine.HCl solution were higher than those after oral administration, whereas the plasma levels of metabolite, morphine-3-glucuronide was lower than those after oral administration. Morphine after rectal administration of Witepsol H-15 suppository released more easily than other suppositories. The inter-animal variation in the plasma levels of morphine after rectal administration of Witepsol H-15 suppository was smaller than those of other suppositories. Results obtained in this study indicate that morphine.HCl suppository prepared with Witepsol H-15 is a promising material as preparation of suppositories.