Pharmacokinetics, Metabolism, and Excretion

Egawa et al. [103] by using a microbial assay method reported that miconazole was not detected in the blood after human subjects were given 100 mg tablets of miconazole intravaginally for 14 days. Six species of 12 strains of human vaginal Lactobacillus were insensitive to miconazole. 

Daneshmend [104] measured the serum concentration of miconazole in 11 healthy adult females for 72 h following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 pg/L and the mean elimination half-life was 56.8 h. The mean area under the serum concentration-time curve was 967 pg/L/h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidiasis. 

Piel et al. compared the intravenous pharmacokinetics of miconazole in sheep after its administration in a polyoxyl-35 castor oil/lactic acid mixture, a 100 pM hydroxylpropyl-/l-cyclodextrin-50 pM lactic acid solution, and a 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin 50 pM lactic acid solution. Intravenous administration of 4 mg/kg of miconazole was completed within 5 min [108]. There were no differences of the miconazole blood plasma concentration versus time for the three dosage forms. The half-life of distribution was 2.4 min. Both hydroxylpropyl-/ - 

Piel et al. [109] studied the pharmacokinetics of miconazole after intravenous administration to six sheep (4 mg/kg) of three aqueous solutions - a marketed micellar solution containing polyoxyl-35 castor oil was compared with two solutions both containing 50 pM lactic acid and a cyclodextrin derivative (100 pM hydro-xylpropyl-/l-cyclodextrin or 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin. This work demonstrated that these cyclodextrin derivatives have no effect on the pharmacokinetics of miconazole by comparison with the micellar solution. The plasma concentration-time curves have shown that there is no significant difference between the three solutions. 

Ohzawa et al. [Ill] studied the metabolism of miconazole after a single oral or intravenous administration of 14C miconazole at a dose of 10 mg/kg. After 1 h oral or intravenous administration to male rats, the four known metabolites besides the unchanged form were observed in the plasma, and the five unknown metabolites were observed in the plasma. At 24 h, metabolites were not detected in plasma except one of the known metabolites. After oral administration to female rats, the unchanged form and four of the known metabolite along with one of the unknown metabolites were observed in the plasma, but one of the known metabolites and three of the unknown metabolites were not detected. After oral or intravenous administration to male rats, two of the known metabolites and five of the unknown metabolites were observed in the urine collected until 24 h. After oral or intravenous administration to male rats, four of the known metabolites and five of the unknown metabolites and one of the known metabolites besides the unchanged form were observed in the feces collected until 24 h. The fecal excretion of the major known metabolite, within 24 h after oral or intravenous administration was 19.4% or 13.3% of the administered radioactivity, respectively. One of the unknown metabolite was isolated from plasma after oral administration to female rats. 

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N. Bodor, T. Loftsson, W. M. Wu, Metabolism, Distribution, and Transdermal Permeation of a Soft Corticosteroid, Loteprednol Etabonate , Pharm. Res. 1992, 9, 1275-1278 N. Bodor, W. M. Wu, T. Murakami, S. Engel, Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats , Pharm. Res. 1995, 72, 875-879. 

Pharmacokinetics Metabolized and excreted in kidney. Half-life 4-7 hr. 

Stass H, Kern A. Moxifloxacin - review of clinical pharmacokinetics metabolism and excretion. In 6th International Symposium on New Quinolones Abstract No. 132. Denver, Colorado, 1998. 

Slatter JG, Schaaf LJ, Sams JP, Feenstra KL, Johnson MG, Bombard PA, Cathcart KS, Verbnrg MT, Pearson LK, Compton LD, Miller LL, Baker DS, Pesheck CV, Lord RS 3rd. Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients. Drug Metab Dispos 2000 28(4) 423-33. 

Perkins EJ, Abraham T (2007) Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15Al)-targeted prodrug (IS, 2S, 5R, 6S)-2-[(2 S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2, 6-di carboxylic acid (LY544344) in rats and dogs assessment of first-pass bioactivation and dose linearity. Drug Metab Dispos 35 1903-1909... 

Sample preparation Vortex 100 irL blood with 200 LL MeCN DMSO 95 5, cool at 0° for several min, centrifuge at 3000 rpm for 10 min, inject an aliquot of the supernatant. (A similar procedure can also be used for bile and urine, see Bodor,N. Wu,W.-M. Murakami,T. Engel,S. Soft drugs 19. Pharmacokinetics, metabolism and excretion of a novel soft corticosteroid, loteprednol etabonate, in rats. Pharm.Res. 1995,12, 875-879.)... 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

Pharmacokinetics refers to activities within the body after a dmg is administered. These activities include absoqrtion, distribution, metabolism, and excretion (ADME). Another pharmacokinetic component is the half-life of the drug. Half-life is a measure of the rate at which drains are removed from the body. 

Pharmacokinetics—The science of quantitatively predicting the fate (disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides the means of studying the absorption, distribution, metabolism and excretion of chemicals by the body. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

Gatz. 1992b. Pharmacokinetics of TBP in rats Section 1 distribution, metabolism, and excretion of 14C-tributyl phosphate. MRI Project No. 9526-F. 

VI. PHARMACOKINETICS OF DRUG ELIMINATED BY SIMULTANEOUS METABOLISM AND EXCRETION... 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

Thus, %F is defined as the area under the curve normalized for administered dose. Blood drug concentration is affected by the dynamics of dissolution, solubility, absorption, metabolism, distribution, and elimination. In addition to %F, other pharmacokinetic parameters are derived from the drug concentration versus time plots. These include the terms to describe the compound s absorption, distribution, metabolism and excretion, but they are dependent to some degree on the route of administration of the drug. For instance, if the drug is administered by the intravenous route it will undergo rapid distribution into the tissues, including those tissues that are responsible for its elimination. 

The pharmacokinetics of rifaximin after oral administration has been studied in healthy volunteers and patients with intestinal infections or IBD. The aim of these studies was to confirm the low, if any, systemic absorption of the drug metabolism and excretion data are scant. In all these investigations a sensitive high-pressure liquid chromatographic (HPLC) method was used to measure rifaximin in body fluids. 

It is important to understand the need for the multiple assays that are now routinely performed by most pharmaceutical companies to measure various absorption distribution metabolism and excretion (ADME) parameters to determine the pharmacokinetic (PK) properties of new chemical entities (NCEs). The goal of new drug discovery is to find NCEs that have the appropriate... 

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