Abstract: The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.

Abstract: In 12 fasting volunteers, the pharmacokinetics of ciprofloxacin (Bay o 9867; 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carbonic acid) were determined after the administration of 50, 100, and 750 mg orally as well as 50 and 100 mg intravenously over 15 min. Serum and urine concentrations were detected with a bioassay. In addition, urine concentrations after a 50-mg dosing were measured by high-pressure liquid chromatography. The serum course of ciprofloxacin could best be described by an open three-compartment model. High volumes of distribution (exceeding 200 liters/100 kg) suggested effective diffusions in the extravascular space. The terminal half-life of ciprofloxacin ranged between 3 and 4 h. High total and renal clearances suggested additional elimination pathways, such as tubular secretion, metabolism, or biliary excretion. After oral administration, absorption was sufficient, and the absolute bioavailability varied between 0.77 and 0.63. Maximal serum concentrations were attained 0.5 to 1 h after dosing; the higher dosage tended towards a delay in absorption. The proportion of the relative amount of metabolites to the total amount of drug excreted in urine increased from 29.7% after intravenous administration to 42.7% after oral dosing, indicating a first-pass effect of the liver. Ciprofloxacin concentrations with a bioassay were 3 to 27% higher than with high-pressure liquid chromatography, which may indicate the presence of biologically active metabolites. No side effects were recorded.

Abstract: Omeprazole has a low water solubility and is chemically labile in an acid environment. In the formulation of an oral dosage form of omeprazole the possibilities of dissolution rate limited absorption and preabsorption degradation must be kept in mind. A water suspension of omeprazole was tested in a pilot bioavailability study. The suspension was given to six healthy, fasting volunteers on two occasions--together with sodium bicarbonate solution and together with the same volume of water. When the suspension was given with water the bioavailability was reduced by about 50% owing to preabsorption degradation. In another bioavailability study the slowest of three granule formulations with differing in vitro dissolution rates showed a reduced extent of absorption. A controlled-release pellet formulation (enteric-coated) was formulated and tested in a series of bioavailability studies. A single dose given with food resulted in a delayed absorption and possibly lower bioavailability than under fasting conditions. When the granules were given on an empty stomach before the morning meal the length of time between dosage and meal was of no importance. Concomitant administration of a liquid antacid had no influence on the bioavailability of omeprazole.

Abstract: We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Abstract: This article reviews the objectives which must be considered in producing optimal formulations for topical ophthalmic use. The effects of preservatives, vehicles, and adjunct agents are described. Anatomical considerations which impact bioavailability of the drug at the desired target site are discussed in detail. Model systems that can aid in determining the best formulations for preclinical and clinical testing are also reviewed. The long term objective of this review is the development of formulations for optimal efficacy and safety, considering all the requirements of the patient.

Abstract: Prichard, R.K., Steel, J.W., Lacey, E. & Hennessy, D.R. Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal, or intraruminal administration. J. vet. Pharmacol. Therap. 8, 88–94. The pharmacokinetics of ivermectin in plasma following intravenous, intra-abomasal, and intraruminal administration to sheep was determined. When given intravenously, ivermectin was very slowly eliminated with a terminal half-life of 178 h and a volume of distribution at steady state of 5.3 l/kg indicating sequestration in a temporary depot. Intra-abomasal administration resulted in rapid absorption, a peak plasma concentration of 6O.6 ng/ml at 4.4 h, and 100% bioavailability. However, intraruminal administration produced a much lower peak concentration (17.6 ng/ml at 23.5 h) and bioavailability (25.1%). A subsequent in vitro study indicated that ivermectin may be rapidly metabolized in the rumen. Dr.J. W. Steel, CSIRO Division of Animal Health, McMaster Lahoratory, Private Bag No. 1, P.O., Glebe, NSW 2037, Australia.

Abstract: Studies have been carried out to investigate the disposition of nicardipine hydrochloride following intravenous and oral administration to male volunteers. Following oral administration of a radiolabelled dose, nicardipine was shown to be rapidly and extensively metabolised and to be rapidly eliminated from plasma. After intravenous infusion of nicardipine at 5 mg-1 for 3 h, plasma levels declined biexponentially, and clearance values were of the same order as hepatic blood flow. With repeated oral administration, 20 mg three times daily for 28 days, plasma levels rose over the first 3 days of administration and then declined to some extent. Possible reasons for this decline are discussed. Steady-state plasma levels and bioavailability show a nonlinear relationship with doses over the range 10-40 mg three times daily. Food consumption has been shown to reduce the bioavailability of nicardipine when the food is taken before or at the same time as nicardipine administration.

Abstract: Bioavailability of an oral preparation of the antineoplastic drug etoposide (VP-16) was studied in 13 patients with advanced malignancies. An initial pilot study involving three patients suggested that approximately 50% of an orally administered dose was absorbed. Ten additional patients were randomized to receive either 100 mg/m2/day iv or 200 mg/m2/day orally. Three weeks later, the alternate dose schedule was administered. Plasma samples were assayed for VP-16 using a high-pressure liquid chromatography technique. Comparison of the area under concentration-time curves (C X t) revealed that 17%-72% (mean, 52%) of an orally administered dose was absorbed. Absorption was less than 40% for only one patient. For oral and iv preparations, mean peak plasma VP-16 concentrations were 9.6 and 13.0 micrograms/ml, mean alpha-half-lives were 0.96 and 0.82 hour, mean beta-half-lives were 7.2 and 6.8 hours, mean C X t values were 75.9 and 75.3 mg/L/hour, mean plasma clearances were 1.44 and 1.45 L/hour/m2, and mean extrapolated volumes of distribution were 15.2 and 16.9 L/m2, respectively. The half-life for oral absorption was 0.44 hour and peak plasma concentrations were noted 0.5-3 hours after oral drug administration. Granulocyte count nadirs tended to be lower in patients with high C X t values and low plasma clearance values. Granulocytopenia was dose-limiting. Gastrointestinal toxicity was extremely mild. We recommend doses of oral VP-16 of 800 mg/m2/course over 3-5 days for patients with a moderate amount of prior treatment. It is probable that previously untreated patients will tolerate a higher dose and that heavily pretreated patients will require a lower dose.

Abstract: We compared the absorption of three formulations of ciprofloxacin after oral administration in 18 normal adult male volunteers. Each subject received 500 mg of ciprofloxacin as two 250-mg tablets, one 500-mg tablet, or a solution in a randomized crossover sequence. Pharmacokinetic parameters were determined by model independent methods. Because a solution is considered to be the ideal oral dosage form, the results determined for the tablets were compared to those for the solution. Mean values for the maximum concentration of drug in serum, the time to maximum concentration of drug in serum, and the elimination half-life were 3.23 micrograms/ml, 1.00 h, and 5.04 h, respectively, for the solution. The mean renal clearance of ciprofloxacin was 372 ml/min and accounted for at least 50% of the total clearance. We recovered 44.4, 48.6, and 55.8% of the administered ciprofloxacin from the urine as unchanged drug within 24 h after dosing with the 250-mg tablets, 500-mg tablets, or solution, respectively. The 500-mg tablets were found to be bioequivalent to the solution with regard to all pharmacokinetic parameters. The 250-mg tablet was not bioequivalent to either of the other formulations; the relative bioavailability values were 78.7 and 74.1%, respectively, for the 500-mg tablet and the solution. The clinical significance of this difference in bioavailability is yet to be determined.

Abstract: The bioavailability of ursodeoxycholic acid (UDCA), a cholesterolic gallstone dissolving agent, has been analysed in seven healthy human volunteers. After absorption of a capsule containing a 500 mg dose, the time course of plasma concentrations of the drug presented a double peak profile over a 240 min period. In order to explain this result, a second group of five subjects bearing a four-way jejunal catheter fitted with an occluding balloon, received an oral dose of 250, 500 or 750 mg of the drug. Simultaneous analyses of plasma UDCA concentrations and jejunal UDCA contents were carried out. UDCA is poorly soluble in the gastro-duodeno-jejunal contents of fasted subjects since 21-50% of the ingested doses were recovered in solid form. The profile of plasma concentration paralleled the amount of soluble UDCA present in intestinal lumen. When jejunal contents were infused below the balloon a second plasma peak appeared in cases corresponding to ingestion of higher doses of UDCA. In conclusion, pharmacological doses of UDCA are not readily soluble in the stomach and intestine of a healthy fasting man. In consequence, the bioavailability of the drug varies with its progressive solubilization in the gastrointestinal tract. The present results suggest that repeated daily doses of UDCA should improve its bioavailability in treated gallstone patients.

Abstract: In recent years, there has been a reduction in caloric intake in populations with decreased energy demands. This has place a greater emphasis on the bioavailability of nutrients in foods because the total intake of nutrients is generally closely linked with total caloric intake. An assessment of the adequacy of dietary intakes of nutrients requires not only knowledge of the nutrient content of the foods ingested but also the extent to which the nutrient present in the diet is available for absorption and utilization. Nutrients ingested but not released during the digestive process for absorption are of no nutritional value. Bioavailability may be considered the relative absorption of a nutrient from the diet. An index of bioavailability may be extended to include the relative accumulation of a nutrient into various tissues. Various nutrients and dietary components interfere with the bioavailability of vitamins. Hence, requirements for vitamins cannot be considered independently, but must be evaluated in relationship to other nutrients and compounds consumed by an individual. An overview has been presented as to the factors that influence the bioavailability of vitamins in the human food supply.

Abstract: Average steady-state propranolol plasma concentration (Css) were calculated from published steady-state propranolol clearance data for dose rates (R0) of 40, 80,160, 240, and 320 mg/day in divided doses every 6 hours. The Css-R0 data for each of four subjects were fit essentially perfectly by the equation: Css = KSSR0/ (Vm — R0). Very similar Vm and Km values were obtained with the Vmi and Kmi values for four parallel Michaelis-Menten pathways of propranolol metabolism. It is shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a first-pass drug that follows Michaelis-Menten elimination kinetics after oral dosing. This most likely explains the poor bioavailability of propranolol after a sustained-release formulation. The decreased bioavailability of propranolol when the number of subdivisions of the daily dose is increased is also explained. Clinical Pharmacology and Therapeutics (1985) 37, 481–487; doi:10.1038/clpt.1985.76

Abstract: A physiologically realistic model is used to provide insight into the design of sampling protocols for accurate determination of AUC(0– ∞) for drugs subject to enterohepatic cycling. Through simulation of plasma concentration- time curves for such drugs it is found that (1) more than one peak is predicted after oral and intravenous administration of a single dose of drug, (2) the relative magnitude of peaks is dependent on the hepatic extraction ratio for both oral and intravenous drug administration, (3) the percent of the AUC(0– ∞) in later time intervals is also a function of the hepatic extraction ratio, and (4) present methods for the design of sampling protocols may not provide accurate estimates of AUC(0– ∞) (especially for highly extracted drugs), because (a) peaks are only evident at later times after intravenous administration when plasma sampling is less frequent, (b) much of the area occurs at later times, and (c) the amount of drug in the sampling compartment after oral administration is much lower than that after intravenous administration of drug and could be incorrectly interpreted as low bioavailability if sampling is not carried out for a long period of time. The types of oral and intravenous profiles predicted for highly extracted drugs are exemplified by data for naltrexone in the monkey.

Abstract: The relative bioavailability of an investigational carbamazepine suspension was studied following rectal administration in human volunteers. Carbamazepine, in doses of approximately 6 mg/kg, was given to nine men. The routes of administration were oral tablet, oral suspension, and rectal suspension. There was no significant difference (p greater than 0.05) in total absorption, maximum serum concentration, and time to achieve maximum serum concentration between the orally-administered tablet and the rectally administered suspension. Orally administered suspension was absorbed more quickly and completely. All volunteers complained of a strong defecatory urge after the suspension was given rectally. The slow absorption after rectal administration precludes the use of this route in status epilepticus; however, it may be a satisfactory alternative for maintenance therapy when administration by the oral route is not possible.

Abstract: The relative and absolute bioavailability of different oral forms of amiodarone was examined in 12 subjects. The doses were 5 mg/kg iv, two 200-mg commercial tablets by mouth, two 200-mg tablets (new formulation) by mouth, and 400 mg in a drinkable solution. Plasma levels of amiodarone and its N-desethylated metabolite were determined by HPLC. Statistical analysis indicated bioequivalence of the oral forms for all the kinetic parameters examined. After oral dosing, amiodarone was slowly absorbed and the maximum plasma level (0.55 +/- 0.20 mg/l) was reached in 4.5 hr. The absolute bioavailability of oral amiodarone was calculated by comparison of AUCs after oral dosing with those after intravenous injection. A mean oral bioavailability of 65% +/- 22% was indicated. Since the tablets were bioequivalent to the drinkable solution, incomplete absorption seems not be a result of the dissolution characteristics of the commercial formulation but rather of a first-pass effect.

Abstract: Six adult patients with squamous cell carcinoma of the head and neck were treated with single low doses of methotrexate (MTX) (30 mg/m2) iv, im, and orally in the form of commercial tablets. A randomized crossover design was employed. Plasma concentrations were measured by a modified EMIT assay over a period of 24 hours following each dose. The mean (+/- SD) parameters following iv MTX were as follows: total-body clearance, 124 (36) ml/minute; Vss, 0.56 (0.18) L/kg; V lambda, 0.69 (0.24) L/kg; and beta-half-life, 3.20 hours. The absolute systemic bioavailability of the oral tablets was 36% (+/- 10%). After im administration, the systemic bioavailability was 93% (+/- 14%). Dose-dependent gastrointestinal absorption is suggested as the mechanism for the low availability of the oral tablets. Administration of MTX by the oral route will require further study to determine the optimal method of dosing.

Abstract: The pharmacokinetics of the analgesic flupirtine (ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamate, D 9998) were examined in healthy volunteers after a single intravenous, peroral and rectal dose. Plasma-and urine concentrations were analysed by a photometric procedure specific for flupirtine and its active metabolite D 13223. The bioavailability from the capsule amounted to 90%, from the suppository to 72.5%. Plasma half-life was 8.5-10.7 h. No significant accumulation of the plasma concentrations after multiple peroral administration was observed. After a peroral dose of 14C-flupirtine the radioactivity is predominantly excreted via the urine (72%). Two metabolites could be isolated from urine and their chemical structure determined. Together with the parent drug they explain 54% of the urinary radioactivity. The metabolite D 13223 that still has some analgesic activity is found in plasma, too. The portion of unchanged flupirtine amounts to 56-83% of the total plasma levels.

Abstract: Five volunteers, whose ages ranged between 37 and 64 years, took part in a crossover study to determine the pharmacokinetics and bioavailability of mebendazole in man following intravenous and oral administration of a tracer dose of [3H]-mebendazole. Following intravenous administration, the average distribution half-life, elimination half-life and rate of clearance were 0.20 h, 1.12 h, and 1.063 min respectively. After oral administration of the solution, the average elimination half-life was 0.93 h, the apparent rate of clearance was 0.846 l/min, the average time to peak plasma concentration was 0.42 h, and the bioavailability of mebendazole was 22%. Comparison of metabolite area under the plasma concentration vs time data from each route of administration indicates that absorption of mebendazole from the gastrointestinal tract at this dose level is almost complete. The low bioavailability observed following oral administration at this dose level is postulated to be due to high first pass elimination. Approximately half of the administered dose of radioactivity following intravenous and oral administration was detected in the urine, and the major unconjugated metabolite of mebendazole was found to be 2-amino-5(6) [alpha-hydroxybenzyl]benzimidazole (IV), not 2-amino-5(6)benzoylbenzimidazole (II), as previously reported.

Abstract: Abstract Many synthetic pesticides (herbicides, insecticides, fungicides, etc.) can be complexed with cyclodextrins. This “molecular encapsulation” frequently results in advantageous modifications of the properties of complexed substances. The hydrophilicity is strongly reduced, i. e. wettability, rate of dissolution and extent of solubility is enhanced, which generally results in enhanced bioavailability. Volatile, liquid, and gaseous substances, or substances of intolerable stink can be converted into microcrystalline, stable, well formulable substances. Incompatible substances can be mixed when at least one of the reacting components is complexed. The selectivity between herbivorous/non‐herbivorous insects toxicity can be enhanced. CD‐complexes are per se micronized substances, they are easily dispergable, no electric charging was observed. Long lasting effect can be ensured ( e. g. in soil) because the complexed substances are released only on contacting with water. Cyclodextrins exert a direct auxin‐like effect on plants therefore phytotoxic effect of pesticides can be reduced, etc . .

Abstract: An oral pharmaceutical composition which comprises a polyglycerol ester of an unsaturated fatty acid and a drug which is very slightly soluble in water.