Predominant Route Of Elimination Research Articles

Metabolic fate of midodrine. (I). Absorption and excretion.

Absorption and excretion of 14C-labeled midodrine were compared with those of 14C-DMAE, which is active metabolite of midodrine, after oral administration of each compound at equimolar dose (3.4 μmol/kg) in rats and dogs. Absorption of 14C-midodrine in rats has been shown to occur mainly from the intestine, and was faster than that of 14C-DMAE. During the process of absorption, DMAE was formed extensively by cleavage of the glycine molecule of midodrine. After oral administration of 14C-midodrine, the peak blood level of radioactivity was attained at 0.5 hr in rats and 1.25 hr in dogs, and was followed by a biexponential decline. In dogs given 14C-midodrine orally, the peak plasma level of unchanged midodrine, accounted for 14 % of total radioactivity, and was attained 0.75 hr after dosing, thereafter declined with a half-life of 4.71 hr. The active metabolite DMAE appeared in the plasma over the same period and the levels exceeded those of unchanged midodrine 0.75 hr after administration. The AUC value of DMAE (AUCDMAE) after administration of 14C-midodrine was apparently higher than that after 14C-DMAE dosing in dogs. In both species, urinary excretion was the predominant elimination route accounting for 89.0 % of the dose in rats and 97.4 % in dogs during 5 days after dosing. Biliary excretion accounted for 28.7 % of the dose in rats within 30 hr after oral dosing. In addition, enterohepatic circulation was demonstrated. Similar excretion profiles were observed in the case of 14C-DMAE.

Biliary excretion of novel pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline

W. M. Lafranconi, S. Ohkuma and R. J. Huxtable. Biliary excretion of novel pneumotoxic metabolites of the pyrrolizidine alkaloid, monocrotaline. Toxicon 23, 983–992, 1985. — Perfusion of the pyrrolizidine alkaloid, monocrotaline, through the isolated rat liver resulted in the appearance of Ehrlich-positive metabolites in both the perfusate and bile. Livers from male rats released greater quantities of metabolite into both bile and perfusate. Metabolite release was stimulated by pretreatment with phenobarbital. Livers of phenobarbital-pretreated male rats perfused with 300 μM monocrotaline produced biliary metabolite concentrations in excess of 5 mM. Metabolite release was inhibited by anoxic perfusion; low temperature and pretreatment with SKF-525A. Above 150 μM monocrotaline, bile became the predominant route of excretion. On perfusion through the isolated lung of the rat, bile and perfusate metabolites were equally effective in inhibiting serotonin transport. A single Ehrlich-positive peak was obtained on silica gel column chromatography of bile containing metabolite. Mass spectrometry revealed the major component of this peak to have a molecular weight of 281, indicating a novel pyrrole metabolite in which the esterifying acid present in monocrotaline, monocrotalic acid, had been partially degraded. This compound mimics the pneumotoxic action of monocrotaline giver, in vivo, and its availability should prove a valuable tool in the elucidation of the mechanism of pyrrolizidine toxicity.

Update on acyclovir: Oral therapy for herpesvirus infections

The results of the major human clinical trials on oral acyclovir are reviewed, and the pharmacokinetics, adverse effects, and role of oral acyclovir in the management of herpes simplex virus (HSV) infections are discussed. Clinical studies have demonstrated the effectiveness of oral acyclovir in causing significant reductions in the duration of viral shedding, development of new lesions, and time to crusting and healing in several clinical situations. The drug appears to achieve the most dramatic results in the treatment of initial primary genital herpes infections. Oral acyclovir also has a potential role in suppressing reactivations of HSV infections in immunocompromised patients or patients experiencing greater than 10-12 recurrences of genital herpes per year. Most trials have used 200-mg capsules administered five times daily for 5-10 days for treating acute infections. Reduced doses have been successful for suppressive therapy. Acyclovir does not alter the frequency of recurrence once treatment has been discontinued. The absolute bioavailability of oral acyclovir is approximately 20%, and plasma concentrations are about one tenth of those achieved after a typical i.v. infusion. The relationship between plasma concentration and clinical response has not been established. The half-life is 3-4 hours, and the predominant route of elimination is via renal excretion and tubular secretion. Clinical studies have consistently reported minimal adverse effects with oral acyclovir. Conservative use is justified by the potential development of resistant viral strains. The extent and clinical importance of resistant viral selection remain to be determined. Oral acyclovir represents an advance in the development of a nontoxic antiviral agent suitable for both hospitalized and ambulatory patients that should be recommended for formulary inclusion.

Preclinical studies of indapamide, a new 2-methylindoline antihypertensive diuretic

Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current and the transmembrane influx of calclum. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with billary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.

109Cadmium Absorption, Excretion, and Tissue Distribution Following Single Tracer Oral and Intravenous Doses in Young Goats

Cadmium metabolism was studied in six 2.5-month-old goats following a single oral or intravenous tracer dose of 109Cd. Whereas, more than 90% of the oral dose was excreted in the feces within five days after dosing, only 5.6% of the intravenous dose was excreted via feces during this time. Feces was the predominant route of excretion regardless of method of dosing. Following a peak level of endogenous excretion on the second day after intravenous dosing, there was a very sharp reduction ia rate of endogenous excretion so that 12 days after dosing endogenous excretion was only 7% of the peak. Fourteen days after intravenous dosing, highest concentrations were observed in the liver, kidney, and spleen, in descending order. In contrast, following oral dosing highest concentrations were found in the small intestine wall, kidney, and liver. A much higher level of 109Cd was found in the liver, heart, and spleen of intravenously dosed animals relative to other tissues than in orally dosed ones. It is theorized that intravenously administered cadmium is transported in a different form from that absorbed from the gastrointestinal tract and that this materially affects cadmium metabolism.