Lipid-soluble drugs metabolites

Following their formation in the hepatopancreas, metabolites are usually excreted in feces and urine, antennal gland, or other sites. Available data indicate that drugs that are readily soluble or can be biotransformed into water-soluble conjugates are more rapidly excreted from crustaceans than lipid-soluble drugs. Hence, very lipophilic drugs can be expected to attain much higher concentrations in the hepatopancreas than in other tissues, and to be slowly excreted in feces after metabolism to more polar metabolites. 

CYP450s include steroid hormones and lipid-soluble drugs (Brown, 2001). Oxidative reactions frequently lead to the formation of highly reactive epoxides. These toxic metabolites are usually detoxified rapidly by phase II conjugation or other mechanisms, such as microsomal epoxide hydrolases (Pineiro-Carrero and Pineiro, 2004 Watkins, 1999). 

Benzodiazepines, like most lipid-soluble drugs, undergo biotransformation to more water-soluble glucuronide compounds, which are eventually eliminated in the urine. The primary metabolites of diazepam (N-desmethyldiazepam) and midazolam (a-hydroxymidazolam) are pharmacologically active, with similar potency to their parent compounds. These active metabolites are probably of little clinical significance after i.v. administration, because of their rapid elimination and the significance of redistribution in the termination of the CNS effect. 

Drugs are eliminated from the body either unchanged by the process of excretion or converted to metabolites see Chapters 2 and 3). Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high hpid solubility. Lipid-soluble drugs thus are not readily eliminated until they are metaboUzed to more polar compounds. 

As drug residue science is concerned with metabolites, as well as parent molecules, it should be noted that most (especially phase II) metabolites are more polar, less lipid-soluble, and less biologically active than parent drugs. Hence, most metabolites follow the general rules on disposition (poor penetration of cell membranes) and elimination (high concentrations in urine and/or bile) applicable to poorly lipid-soluble drugs. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Hemoperfusion is like hemodialysis except that blood is circulated extracorporeally through a column with adsorbent material like resin or charcoal, which binds molecules electrostatically. The molecules likely to be removed are characterized as poorly dialyzable, lipid-soluble, protein bound. Among the indications for hemoperfusion in the management of poisoning include the presence of a poison in a patient with impairment of excretory system (i.e. damaged kidneys), intoxication of a drug known to produce delayed toxicity or metabolized to a more toxic metabolite (i.e. paraquat or methotrexate), deterioration of the clinical state of the poisoned patient despite conservative therapy (i.e. convulsions or cardiac arrhythmias following theophylline intoxication), or development of coma as a complication. 

Once first-pass metabolism has occurred, metabolites are excreted into the bile and then the small bowel. Those that are lipid soluble are reabsorbed into the portal circulation, eventually entering the systemic circulation. These metabolites may have a similar or substantially different pharmacological profile from their parent drug. For example, chlorpromazine undergoes extensive hepatic biotransformation and has 168 theoretical metabolites, 70 of which have been identified in plasma and... 

---