Cefuroxime axetil is a new orally absorbed prodrug of the antibiotic cefuroxime. The results of pharmacological studies in 52 healthy volunteers are presented. Intact cefuroxime axetil was not detected in the systemic circulation, indicating that deesterification to yield cefuroxime occurs rapidly after absorption. The bioavailability as measured by urinary recovery of cefuroxime was 40 to 50% if the drug was taken after food and 30% if the drug was taken after overnight fasting. Absorption was similar for three different formulations at 500 mg and independent of dose over the range of 250 mg to 1 g. When the drug was taken after food, serum levels and urinary recoveries were significantly greater for cefuroxime than for ampicillin, but when the drug was taken after fasting the values were similar for the two drugs. The kinetic behavior of cefuroxime axetil and ampicillin was not influenced by repeated dosing at 250 mg. Cefuroxime axetil was well tolerated. Although changes in bowel flora and habit were noted during repeated dosing, these changes were no greater than with ampicillin.

Pharmacology of Cefuroxime as the 1-acetoxyethyl ester in volunteers.

Kinetics and mechanism of in vitro uptake of amino-β-lactam antibiotics by rat small intestine and relation to the intact-peptide transport system

Individual variation in pharmacokinetics has long been recognised. This variability is extremely pronounced in drugs that undergo extensive first-pass metabolism. Drug concentrations obtained from individuals given the same dose could range several-fold, even in young healthy volunteers. In addition to the liver, which is the major organ for drug and xenobiotic metabolism, the gut and the lung can contribute significantly to variability in first-pass metabolism. Unfortunately, the contributions of the latter 2 organs are difficult to quantify because conventional in vivo methods for quantifying first-pass metabolism are not sufficiently specific. Drugs that are mainly eliminated by phase II metabolism (e.g. estrogens and progestogens, morphine, etc.) undergo significant first-pass gut metabolism. This is because the gut is rich in conjugating enzymes. The role of the lung in first-pass metabolism is not clear, although it is quite avid in binding basic drugs such as lidocaine (lignocaine), propranolol, etc. Factors such as age, gender, disease states, enzyme induction and inhibition, genetic polymorphism and food effects have been implicated in causing variability in pharmacokinetics of drugs that undergo extensive first-pass metabolism. Of various factors considered, age and gender make the least evident contributions, whereas genetic polymorphism, enzymatic changes due to induction or inhibition, and the effects of food are major contributors to the variability in first-pass metabolism. These factors can easily cause several-fold variations. Polymorphic disposition of imipramine and propafenone, an increase in verapamil first-pass metabolism by rifampicin (rifampin), and the effects of food on propranolol, metoprolol and propafenone, are typical examples. Unfortunately, the contributions of these factors towards variability are unpredictable and tend to be drug-dependent. A change in steady-state clearance of a drug can sometimes be exacerbated when first-pass metabolism and systemic clearance of a drug are simultaneously altered. Therefore, an understanding of the source of variability is the key to the optimisation of therapy.

Individual Variation in First-Pass Metabolism

Publisher Summary This chapter presents the experimental work to evaluate the potential for a nutrient prodrug approach to overcome problems in oral drug delivery that has been carried out with several compounds at various levels of biological system complexity. Targeting for both intestinal pancreatic enzymes as well as brush border enzymes has been investigated with derivatives of drug carboxyl, amino, and hydroxyl functionalities. The results indicate that prodrugs targeted for intestinal peptidases as well as those targeted for intestinal alkaline phosphatase show potential for improving oral drug delivery. For the stable phosphate derivatives, axial enzyme distribution in different species should determine the relative success for these prodrugs. For those prodrugs targeted for intestinal peptidases, prodrug instability and enzyme specificity with respect to targeting to gain transport advantages for oral administration are key considerations for the utility of this approach. Amino acid esters of drugs have been suggested as prodrugs for modifying drug solubility, dissolution rate, gastric irritation, and chemical stability.

[28] Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting

Pseudomonas aeruginosa-catecholamine inotrope interactions: a contributory factor in the development of ventilator-associated pneumonia?

The radioactive metabolites of D-and L-isomers of 3, 4-dihydroxyphenylalanine-(DOPA)-2-14C in the urine and the main tissues were comparatively investigated after intravenous and oral administration to rats. After administration of L-DOPA, eighteen metabolites were detected in the urine and dopamine conjugate, dopamine, homovanillic acid (HVA), 3, 4- dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenyl ethanol (MHPE) conjugate were found to be the main metabolites, while excretion as DOPA was only less than 1%. After administration of D-DOPA, an appreciable amount (20%) was excreted as unchanged DOPA, but dopamine, mostly in the free form, was found to be the main metabolite. After administration of L-DOPA, dopamine and its metabolites were the main component in the tissues including the brain and skeletal muscle, while after that of D-DOPA, 3-O-methyl-DOPA was the only metabolite, except the kidney where dopamine and its metabolites were found to be formed. It was demonstrated that approximately 67 and 53% of the brain radioactivity was dopamine and its metabolites at 10 and 60 min after intravenous and oral administration of L-DOPA-14C, respectively. The main metabolite in the pancreas and intestine from L-DOPA was DOPAC and dopamine conjugate, respectively, while unchanged DOPA from D-DOPA. In the liver, where D-DOPA dose not accumulate, dopamine conjugate was the main metabolite from L-DOPA, while no dopamine from D-DOPA. From these results, D-DOPA was considered to be metabolized to dopamine only in the kidney, most of which is excreted directly into the urine.

Studies on the Metabolism of D-and L-Isomers of 3, 4-Dihydroxyphenylalanine (DOPA). IV. Urinary and Tissue Metabolites of D- and L-DOPA-14C after Intravenous and Oral Administration to Rats

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Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). 3. Absorption, distribution and excretion of D- and L-DOPA-14C in rats following intravenous and oral administration.

The intestinal absorption and the site for hydrolysis of pivampicillin were compared with those of ampicillin by in situ ligated loop method in rats, using the radioactive compounds labeled at the phenylglycyl and the oxymethylene moieties. It was shown that pivampicillin is well absorbed from all parts of intestine, while ampicillin is absorbed from a more limited part of intestine. Pivampicillin was found to be rapidly transferred from the lumen into the intestinal wall as an intact ester and was hydrolyzed rapidly in the tissue. Ampicillin thus formed appeared to be transitorily accumulated in the tissue before being transferred into the portal venous blood gradually. Ampicillin was absorbed slowly without any accumulation in the intestinal wall. Microautoradiography of pivampicillin-14C in the intestine demonstrated that the radioactivity is accumulated in the epithelial cells in a high concentration. Histochemical and cytochemical detection of non-specific esterase revealed that a high activity is located specifically in the epithelial cells of villi and that the activity is localized in the membranes of endoplasmic reticulum as well as the cytoplasm, while there was almost no activity in the microvilli and terminal web region. It is considered therefore that pivampicillin is penetrated into the epithelial cells without any cleavage of the ester group and hydrolyzed by non-specific esterase in the apical cytoplasm of the cells. When the esterase activity was compared histochemically in rats, dogs and monkeys, it was found that the activity was extremely weak in dog intestine, providing an explanation for the fact that intact pivampicillin was detected in the portal venous blood only in dogs after oral administration. A possible relation between these results and the fact that a hepatic toxicity of pivampicillin was observed only in dogs among these animals was pointed out and discussed.

Studies on intestinal absorption of pivampicillin and species difference in the intestinal esterase activity

Pancurofnium bromide and its deacetylated metabolites were determined in human urine after intravenous administration to five patients by two methods : ion-pair extraction with bromophenol blue for the quaternary nitrogen and hydroxamic acid method for the acetyl group. Succinylcholine which was administered simultaneously was confirmed not to be extracted as the ion-pair complex at all. For the assay of the acetyl group, pancuronium and its metabolites were isolated from the urine as the ion-pair complex followed by column chromatography. The extracts were also subjected to silica gelthin-layer chromatography, wherein pancuronium and its three deacetylated metabolites could be separated while the dye went away to the top of the plate. The results revealed that approximately 20 to 50% of the dose was recovered in the urine during 24 hr period after administration, mostly in the first 3 to 4 hr period, and that pancuronium was excreted mainly as the unchanged form with a slight amount of its mono- and dihydroxy metabolites. The extractability of quaternary ammonium ions with a wide variety of structure as ion-pair complex with bromophenol blue was examined in order to find any relation to the structure. It was revealed that the extractability is determined mainly by two factors, that is, the lipophylic character of the ammonium ion and the steric effect around the cationic head and the value of the sum of π-constants for four groups plus that of Es parameters for three smallest groups can provide an approximate measure for predicting the extractability.

Determination of pancuronium bromide and its metabolites in human urine by dye-extraction method--relation between the extractability and structure of quaternary ammonium ions.

The intestinal absorption of 14C-oxazolam was studied by means of rat ligated loop technique and the metabolites in the intestine, liver, blood and brain were followed by thin-layer chromatography. The results indicated that oxazolam is very easily absorbed from almost whole part along the rat intestine, with the fastest rate from the upper part of the small intestine and is transferred from the lumen into the blood stream mostly in the form of unaltered oxazolam. It was also clarified that a large part, approximately 60%, of the drug absorbed is brought back into the intestinal lumen through the biliary excretion and the extent of occurring its reabsorption appears to be insignificant. In the brain, oxazolam was the main component of the radioactivity at the earliest period after the administration, while N-desmethyldiazepam showed a gradual increase with increasing the time concomitant with a decline of the oxazolam level, reaching a maximum at a later period. A possible participation of this metabolite for the duration of anticonvulsant activity of oxazolam was pointed out. It was suggested from in vitro studies that N-desmethyldiazepam was derived from its gradual transfer from the blood circulation into the brain tissue after being formed from oxazolam in the liver microsomal enzyme.

Kazuyo Tanaka

Papers

Studies on the Metabolism of D-and L-Isomers of 3, 4-Dihydroxyphenylalanine (DOPA). IV. Urinary and Tissue Metabolites of D- and L-DOPA-14C after Intravenous and Oral Administration to Rats

Studies on the metabolism of D- and L-isomers of 3,4-dihydroxyphenylalanine (DOPA). 3. Absorption, distribution and excretion of D- and L-DOPA-14C in rats following intravenous and oral administration.

Studies on intestinal absorption of pivampicillin and species difference in the intestinal esterase activity

Determination of pancuronium bromide and its metabolites in human urine by dye-extraction method--relation between the extractability and structure of quaternary ammonium ions.

Studies on the Metabolism of Oxazolam. III. Absorption from Rat Intestine and Metabolites in the Liver, Brain and Blood