Hydrophilic metabolites

Interestingly, okadaic acid diol ester (16) in the culture medium is oxidatively transformed into the more hydrophilic metabolites 18-20 by intact cells of the diatom Thalassiosira weissflogii [52,53]. This transformation is speculated to change the toxic metabolite with allelopathic activity into a less toxic transport form that can be better excreted by the diatom. 

The membrane-attached cytochrome P450 enzymes are involved in a significant fraction of events associated with drug metabolism. Most of the cytochrome P450 (CYP) catalyzed reactions lead to the detoxification of xenobiotics, by forming hydrophilic metabolites that can be readily excreted from the body. 

The radioactivity recovered from water showed the presence of unchanged cis-chlordane in the organic phase along with several hydrophilic metabolites (Fig. 4). Most of the radioactivity in both organic and aqueous phases was in the form of conjugates. 

Biotransformation involves the chemical alteration of a molecule to alter its effects. This often terminates the pharmacological effects of a drug, but active metabolites are produced in some cases. Biotransformation also changes the ease with which a drug is eliminated. This involves conversion of the drug to a more hydrophilic metabolite that enhances renal excretion. Although this process pertains to most drugs, it probably... 

While most lipophilic and large molecules are primarily excreted by the hepatobiliary system, the kidney is the major excretory organ for many small organic and inorganic molecules, drugs and hydrophilic metabolites, maintenance of fluid balance, and bone metabolism. These functions expose the kidney to a number of clinical, physiological, and pathological conditions that may compromise renal function. Some renal disorders that necessitate clinical intervention are listed in Table 2. 

The molecular weight or size of an optimal delivery system in vivo is imposed by the physiology of circulation and excretion. The lower limit of the molecular weight is about 30 kDa because the microtubular cells in the kidney readily excrete hydrophilic molecules whose molecular weight is 30 kDa or less.23 In fact, this is the major route of elimination for many small-molecule drugs after they are transformed into more hydrophilic metabolites. Therefore, a drug delivery system should have a combined molecular weight of 30 kDa to avoid such a quick renal clearance. 

THC undergoes metabolic degradation in the liver, where it is hydroxylated to 11-hydroxy tetrahydrocannabinol (THC-llOH). The latter, still with psychoactive activity, is oxidized to A9-THC-COOH, an inactive metabolite which is conjugated as 1 l-nor-A9-tetrahydrocannabinol-9-carboxy-glucuronide (A9-THC-COOH-glu), more hydrophilic metabolite and therefore easily excreted in the urine [32],... 

Yoshida, H. et al. On-line desalting mass spectrometry system for structural determination of hydrophilic metabolites, using a column switching technique and a volatile ionpairing reagent. J. Chromatogr. A. 2006, 1119, 315-321. 

Drug metabolism is commonly - and somewhat arbitrarily - subdivided into phase I and phase II reactions. In Figure 2.22, phase I would correspond to the conversion of a dmg molecule to a more hydrophilic metabolite. The latter may then either be directly excreted in the urine, or undergo conjugation with a larger polar moiety before excretion. 

Disposition in the Body. Poorly absorbed after oral ingestion but when dissolved in oils or other lipids it is readily absorbed by the skin and gastro-intestinal tract. It is rapidly metabolised in the body by epoxidation to dieldrin dieldrin is stored in the body fat and persists for several weeks after the cessation of exposure. It is slowly eliminated in the faeces, mainly as unknown hydrophilic metabolites a small amount is excreted in the urine as metabolites. 

Conjugation reactions of xenobiotics or their metabolites with endogenous substrates produce highly hydrophilic metabolites however, to a lesser extent functional groups may be also methylated or acetylated to produce less hydrophilic compounds. 

The idea that a cleft is formed in the hydrophobic region of the protein stems from Mitchell s suggestion about a mobile membrane barrier, meant to explain the mechanism of operation of carriers that translocate hydrophilic metabolites [27,28]. Quite recently Mitchell [29] has presented a concrete version of the mobile membrane barrier principle. He assumes that a slight relative shift of a-helical transmembrane columns (e.g., rotation or tilting of the columns at a small angle) may result in the formation of a cleft allowing solutes to reach the membrane core. ... 

A steady flow of metabolites both in and out of the mitochondrial matrix space is necessary for mitochondria to perform functions which involve the participation of enzymes inside the membrane permeability barrier. These functions include oxidative phosphorylation and therefore O2, ADP, phosphate and electron-rich substrates such as pyruvate, fatty acids and ketone bodies must enter the mitochondria, and the products, HjO, CO2 and ATP must leave. Although Oj, HjO and CO2 are permeable to the inner mitochondrial membrane [1,2], most metabolites are not, because of their highly hydrophiUc nature. The outer mitochondrial membrane does not present a significant barrier to hydrophilic metabolites because of the presence of large unregulated channels composed of the membrane protein, porin [3]. The inner mitochondrial membrane has a much larger surface area [4] than the outer membrane and a much higher ratio of protein to lipid [5]. It is composed not only of proteins involved in electron transport and oxidative phosphorylation but also specialized proteins which facilitate, and in many cases provide, directionality to the transport of metabolites [6]. 

Oxidation of primary [Eq. (1)], secondary [Eq. (2)], or tertiary [Eq. (3)] carbon atoms all occur to give the corresponding alcohols. Further oxidation of a primary alcohol yields the aldehyde, which is usually rapidly converted to the carboxylic acid. The oxidation of secondary alcohols to ketones generally leads to less hydrophilic metabolites and is less common. 

Xenobiotics can be absorbed across the cellular barriers and may be biologically active and possibly toxic to the cell. Metabolism of these molecules by enzymes to hydrophilic metabolites is a prerequisite for their eventual elimination from the body. However, in some cases bioactivation may also occur, and such metabolites may be toxic. Xenobiotic metabolism has therefore been widely studied since the early 1800s [1]. The parent molecule and the products of metabolic pathways may also be involved in drug interactions where they... 

Figure 15.23. Design and metabolism of ultrashort-acting ACE inhibitors (95) based on soft analogs of captopril (94). Hydrolytic cleavage of these compounds results in small, hydrophilic metabolites (e.g., 97, 98) that have no ACE inhibitory activity.

Biotransformation Studies. Incubation of 24-hr old monolayer cultures with furazolidone resulted in degradation of the parent compound into a large number of more hydrophilic metabolites (Figure 4A). Only the cyano-metabolite (CN), which was previously detected as a minor metabolite in the blood of treated pigs 80), could be identified. Subsequent studies with this metabolite showed its rther degradation in the cells into a number of other metabolites (Figure 4B) it was hitherto assumed to be a stable terminal metabolite. 

Recently, Matolcsy and Bordas (1969) investigated the trichloromethanesulfenyl derivatives of urazole and 6-azuracyl. Assuming tautomerism of the compounds, the formation of the hydrophilic metabolite may be expected, which means increasing translocation. 

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