Absorption and disposition characteristics of nitrofurantoin in dogs

This study reports the disposition kinetic properties of nitrofurantoin in dogs following single intravenous and oral administration of various formulations of nitrofurantoin. Also reported here is the effect of delaying gastric emptying by food and atropine on the absorption characteristics of nitrofurantoin. The drug absorption parameters calculated using a deconvolution computer program indicate that the rate and extent of enterohepatic recycling affects the elimination and absorption rate constants and thus confound the bioavailability calculations of nitrofurantoin, heretofore unrecognized in the literature. The plasma half-life following intravenous administration was 31 min (monoexponential equation) with little effect of enterohepatic recycling noted. Following oral administration, a biexponential equation with lag-time was used to fit the blood levels. The absorption half-lives were higher when nitrofurantoin was administered as a solid dosage form compared to a solution. The absorption half-lives following tablet administration ranged from 30 to 72 min and were not affected by food or atropine. The elimination half-lives following oral administration ranged from 19 to 87 min with significantly prolonged elimination when solid dosage forms were administered compared to solution. The extent of absorption ranged from 38 to 120 per cent. A direct correlation between the absorption and elimination half-life was established, indicating that increased biliary recycling direct affects the apparent disposition half-life. The three brands of nitrofurantoin tested for bioavailability showed that the use of blood levels without appropriate corrections for biliary recycling are not suitable for bioavailability testing of nitrofurantoin. The use of urinary excretion data in evaluating nitrofurantoin bioavailability is also questioned in the study.     

Nonlinear assessment of nitrofurantoin bioavailability in rabbits

The influence of route of administration on the absolute bioavailability and GI tract absorption of nitrofurantoin was investigated in rabbits. The disposition of nitrofurantoin was described by a one-compartment model with simultaneous first-order and Michaelis-Menten type elimination kinetics, and bioavailability was estimated by nonlinear assessment. The plasma levels following oral administration were significantly lower than those after intravenous administration, and absolute Fvalues for oral administration were approximately 0.3. However, Fvalues following intraduodenal administration and portal vein infusion were nearly unity, and it was concluded that the reduction of bioavailability following oral administration could not be attributed to metabolism by intestinal microflora or to the hepatic first-pass effect. Thus, reduction of Fvalues following oral administration is probably due to gastric degradation of the drug. The effects of factors influencing bioavailability, such as water volume taken with the drug, change of gastric emptying rate and effect of particle size, were also investigated. Increase of volume of water administered tended to improve the bioavailability, and a particle size dependency was also observed.     

Evidence of a flip-flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats

The pharmacokinetics of acamprosate were examined in the rat after oral and intravenous administration in order to detect the possible presence of a flip-flop phenomenon. Rats received 9.3 or 73.3 mg/kg of the drug as an intravenous bolus. The same doses were orally administered via gastric intubation. Plasma samples were taken from the jugular vein for determination of acamprosate concentration by liquid scintillation counting. The drug content was also quantified in urine and faeces. The acamprosate bioavailability was close to 20%, the amount recovered in the faeces being around 80% of the administered dose. The terminal slope of the oral plasma curve was significantly lower than that obtained after intravenous administration of the drug at both doses tested (p<2 x 10(-6) in both cases). Moreover, the downward slope after oral administration (lambda2=0.006 +/- 0.001 min(-1)) practically coincided with the first-order absorption rate constant, previously reported by us, obtained using an in situ rat gut technique. It is concluded that the acamprosate absorption rate is considerably slower than its elimination rate so that the drug exhibits flip-flop pharmacokinetics after oral administration. The lower intrinsic first-order absorption rate constant, ka, is responsible for this phenomenon.     

A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

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.     

Nasal absorption of ergotamine tartrate in rats

The nasal administration of ergotamine tartrate was studied in rats following a single dose of 0.5 mg/rat and compared to intravenous, intraduodenal and oral administration of the drug. The effect of the addition of caffeine on the extent of nasal absorption was also studied. Relative to the 100% bioavailability from the intravenous route, the bioavailabilities were nasal: 62.0%; intraduodenal: 12.7%; and oral: 5.1%. The addition of 2.5 mg/rat of caffeine slightly improved the extent of nasal absorption; however, such an enhancement was found to be statistically insignificant.     

Lipid nanocarriers as drug delivery system for ibuprofen in pain treatment

Due to their small size, lipid nanocapsules (LNC) might be promising for an injectable as well as for an oral drug delivery system, providing both sufficient drug solubility avoiding vessel embolisation for the intravenous injection and a positive effect of drug absorption after oral administration. Biocompatible ibuprofen LNC were developed in a size range of around 50 nm with a new preparation method. Drug incorporation into LNC was successful to a high degree in all formulations tested (94-98%) and the in vitro drug release in phosphate buffer occurred within 24 h. Pharmacokinetic data were recorded in vivo from rats after intravenous or oral administration, while the antinociceptive efficiency of the LNC formulation was compared with ibuprofen solution by the tail flick test. The AUC and half-life of intravenously injected ibuprofen LNC were found to be 16 and 19%, respectively, higher than a simple drug solution, while the mean residence time was not changed. Oral administration of LNC showed an 18% increase of AUC and a 27% higher mean residence time. The antinociceptive effect was similar for oral administration, drug solution, and LNC at 30 min after administration, and was prolonged up to 4 h in the LNC group. The pain relief after intravenous administration was prolonged when administering LNC formulation for at least 2 h. A drug delivery system for intravenous administration of ibuprofen has been developed which exhibits sustained release properties by either oral or intravenous route and may be interesting in the treatment of postoperative pain.     

Absorption and dissolution of nitrofurantoin from different experimental formulations

The general applicability of the polyvinylpyrrolidone, polyethylene glycol, mannitol and sorbitol solid dispersion and co-precipitation technique as a method for enhancing the gastrointestinal absorption of orally administered hydrophobic drugs was explored with the urinary antiseptic nitrofurantoin. The in vivo absorption patterns of pure nitrofurantoin and the test preparations were compared by following the cumulative amount of nitrofurantoin excreted in the urine as a function of time. The results of these urinary excretion studies demonstrated that the absorption of nitrofurantoin in man from the test systems was significantly enhanced and was present in the body at much higher levels than when equivalent doses of either the drug alone or as physical mixture were orally administered. A correlation was found between the in vitro dissolution rates of these test systems at 37°C and their in vivo absorption data.     

Evaluating drug absorption after oral administration. Some problems and some solutions

Summary Quantitative assessment of drug absorption remains a difficult task, because the multiple-compartment disposition of a drug may not be obvious after oral administration (the problem of the vanishing exponential) and the macroconstants are indistinguishable. For these reasons, proper analysis of the drug absorption based on the apparent behavior of oral data without intravenous reference curve rarely provides absorption information useful for in vivo — in vitro correlations. When intravenous reference curve is available, compartment model used for analysis of the oral data should be corresponding to the iv data such as the Loo-Riegelman method. The model independent statistical moments method is one of the preferable alternatives because of its ease of computation and its potentially smaller error, if absorption can be assumed to be first-order.     

Pharmacokinetics and bioavailability of intravenous,oral, and rectal nitrazepam in humans

The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.     

Generalizations in linear pharmacokinetics using properties of certain classes of residence time distributions. II. Log-concave concentration-time curves following oral administration

The present approach enables a noncompartmental assessment of log-concave plasma concentration-time profiles following oral drug administration. Observed log-concavity corresponds to a nonparametric class of residence time distributions with the following properties: (1) The fractional rate of elimination kB(t) (failure rate of the distribution) increases monotonically until reaching the terminal exponential coefficient kB,Z. (2) The relative dispersion of body residence times CVB2 (ratio of variance to the squared mean, VBRT/MBRT2) acts as a shape parameter of the curve. The role of the input process in determining the shape of the concentration profile is discussed. In this connection evidence is provided for the importance of log-concave percent undissolved versus time plots, introducing the general concept of a time-varying fractional rate of dissolution. The governing factor for the appearance of log-concavity is the ratio of mean absorption time to mean disposition residence time (MAT/MDRT); this factor exceeds a particular threshold value which depends on the distributional properties of the drug. Generalizing previous approaches which are valid for first-order input processes, the "flip-flop" phenomenon and the problem of "vanishing of exponential terms" are explained using fewer assumptions. Upper bounds for the elimination time (more than 90% eliminated) and the cutoff error in AUC determination are presented. The concept of log-concavity reveals general features of the pharmacokinetic behavior of oral dosage forms exhibiting a dominating influence of the absorption/dissolution process.     

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.     

Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine-N-oxide following i.v. and oral administration in healthy volunteers.

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine-N-oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/- 13.7%. Following intravenous administration, the mean AUC0-8 h metabolite/AUC 0-8 h pinacidil ratio was 0.559 +/- 0.272 and after oral administration, 0.825 +/- 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half-life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine-N-oxide may be a 'first-pass' metabolite of pinacidil. In most patients pinacidil pyridine-N-oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.     

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure-pharmacokinetic relationships

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.     

Diuretic effect and disposition of furosemide in cystic fibrosis

Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis.The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug.The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects.The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.     

Further studies on nitrofurantoin excretion in dog hepatic bile

1. Results obtained with a dog donor-recipient model indicate that following intravenous administration of nitrofurantoin sodium, nitrofurantoin is subjected to enterohepatic cycling. At least one-third of the nitrofurantoin originally excreted in the donors' bile after a nitrofurantoin dose of 3 mg/kg is reabsorbed intestinally in the recipients within 3 hours.2. After intraduodenal administration of a nitrofurantoin suspension to dogs at doses ranging from 2 to 12 mg/kg, about 10% of the dose is recovered in bile as nitrofurantoin within 6 hours. A hydrocholeretic effect was also observed which correlated with the amount of drug administered. Both biliary drug excretion and the related hydrocholeresis appeared linearly related over the drug dose range.3. The hydrocholeresis observed in dogs within 3 h after intravenously administered nitrofurantoin sodium, equivalent to 3 mg/kg nitrofurantoin, was at least ten times that seen following the intravenous administration of an equimolar dose of dehydrocholic acid given as its sodium salt.     

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.     

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.     

Mean time and first-pass metabolism

Summary The theoretical principles are outlined for estimating the fraction of a drug undergoing first-pass metabolism using only the plasma levels found after a single oral dose. Data for 3 drugs are used to illustrate the method. It involves analysis of the parent drug and the metabolite formed during the first passage through the gut wall and liver and evaluation of their total mean times. The mean time characteristics of molsidomine, nortriptyline and propranolol are considered and they confirm the theoretically deduced dependency of the mean time of the parent drug and the metabolite. Whether the results are more precise than those obtained from comparison of areas after oral and intravenous administration is discussed. From the data presented it is clear that the mean time method depends on the scatter inherent in the data. In order to estimate the true first-pass effect, greater scatter requires an increased number of data pairs, i.e. subjects. If intravenous data are not available, however, the method described provides a rough but worthwhile estimate of the first pass effect.Dedicated to Professor Dr. H.J. Dengler, Bonn, on the ocassion of his 60th birthday     

In‐situ absorption,protein binding and pharmacokinetic studies of S002‐853, a novel antidiabetic and antidyslipidaemic flavone derivative in rats

Objectives The aim of the study was to investigate the in‐situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002‐853, which shows pronounced antidiabetic and antidyslipidaemic activity. Methods Quantification of S002‐853 in plasma was performed by the LC‐MS/MS method and in‐situ sample analysis was carried out by the HPLC‐UV method. Key findings The absorption rate constant was 0.274/h in a mild alkaline environment, which S002‐853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 ± 2.58% at a concentration of 1 μg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C_max) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration–time profiles with secondary peaks were observed after oral dose administration. The elimination half‐life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002‐853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation. Conclusions In‐situ study of S002‐853 shows slow absorption from the gastrointestinal tract. S002‐853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.