Liver metabolizing systems

Migliore, L., Rossi, A.M. Loprieno, N. (1982) Mutagenic action of stracturally related alkene oxides on Schizosaccharomyces pombe the influence, in vitro , of mouse-liver metabolizing system. Mutat Res., 102, 425 37 Montaldo, C., Dore, M. Congiu, L. (1984) Glycidol, a new depletor of hver glutathione. 

The pharmacist should certainly know which drug dosage forms have been designed as delivery systems for prodrugs and also understand the mechanism whereby the active form is made available within the body. Only then can the pharmacist counsel the physician about why a certain product may be inappropriate for such individuals as an achlorhydric patient, a patient with a gastrectomy, or even possibly a patient with a hepatoportal bypass, if liver metabolism... 

Among common in vitro metabolizing systems, liver microsomes and liver S9 fractions are used more often in metabolite synthesis than other systems. The majority of drug metabolism is mediated by CYPs [8]. Liver microsomes contain a high concentration of CYPs and other... 

Lidman, U., F8rlin, L., Molander, 0. and Axelson, G. Induction of the drug metabolizing system in rainbow trout (Salmo gairdnerii) liver by polychlorinated biphenyls (PCBs). Acta Pharmacol, et Toxicol. (1976) 39., 262-272. 

Each hormone is the center of a hormonal regulation system. Specialized glandular cells synthesize the hormone from precursors, store it in many cases, and release it into the bloodstream when needed (biosynthesis). For transport, the poorly water-soluble lipophilic hormones are bound to plasma proteins known as hormone carriers. To stop the effects of the hormone again, it is inactivated by enzymatic reactions, most of which take place in the liver (metabolism). Finally, the hormone and its metabolites are expelled via the excretory system, usually in the kidney (excretion). All of these processes affect the concentration of the hormone and thus contribute to regulation of the hormonal signal. 

The skin not only is a barrier to restrict diffusion of chemicals into the body, it is also an organ that can metabolize a variety of topically applied substances before they become systemically available. The skin has many of the same enzymes as the liver. The activities of several cutaneous enzymes in whole skin homogenates have been measured and compared to hepatic activity in the mouse. The activities of the enzymes in the whole skin homogenates were typically 2-6% of the hepatic values. However, there is evidence that the enzymes are present primarily in the epidermis. Because the epidermis makes up only 2-3% of the total skin, the real activities may range from 80% to 240% of those in the liver. Enzyme systems present include a qrtochrome P-450 system and a mixed-function oxidase system. 

Glende EA. 1972. Carbon tetrachloride-induced protection against carbon tetrachloride toxicity. The role of the liver microsomal drug-metabolizing system. Biochem Pharmacol 21 1697-1702. 

Mecfianism of Action An ergotamine derivative, alpha-adrenergic blocker that directly stimulates vascular smooth muscle. May also have antagonist effects on sero-fonin. Therapeutic Effect Peripheral and cerebral vasoconstriction. Pharmacokinetics Slow, incomplete absorption from the gastrointestinal (GI) tract rate of absorption of intranasal route varies. Protein binding greaterthan 90%. Undergoes extensive first-pass metabolism in liver. Metabolized to active metabolite. Eliminated in feces via biliary system. Half-life 7-9 hr. 

Tipranavir is a newer PI for treating patients with resistance to other PI agents. Bioavailability is poor but is increased when taken with a high-fat meal. The drug is metabolized by the liver microsomal system. Tipranavir must be taken in combination with ritonavir to achieve effective serum levels. It is contraindicated in patients with hepatic insufficiency. Tipranavir contains a sulfonamide moiety and should not be administered to patients with known sulfa allergy. 

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54-4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin s... 

Thus, fetal liver from primates has a more well-developed metabolic system for xenobiotics than does that from rodents and rabbits, for example. This may be due to the late development of the smooth endoplasmic reticulum and therefore of cytochrome(s) P-450 in the latter species. The use of metabolic inducers and inhibitors in vivo and the use of metabolizing systems with embryo or limb bud culture in vitro have all indicated that for some teratogens,... 

Phenol induced mutations at the hprt locus of Chinese hamster V79 cells in the presence of an exogenous metabolic system from the livers of phenobarbital-induced mice and tk locus mutations in mouse lymphoma L5178Y cells in the presence or the absence of an exogenous metabolic activation system. Micronuclei were induced by phenol in Chinese hamster ovary cells in one study and sister chromatid exchanges in mammalian cells were increased in several studies, including three with human lymphocytes. 

In vitro, in the absence of an exogenous metabolic system, 2-nitropropane induced unscheduled DNA synthesis in rat and mouse liver cells. It induced gene mutations in Chinese hamster cells and rat hepatoma cells in the absence of an exogenous metabolic system. In the absence of an exogenous metabolic system, 2-nitropropane induced micronuclei in three rat hepatoma cell lines but not in Chinese hamster cells. 

Vinylidene fluoride is taken up rapidly via the pulmonary route in rats, but at equilibrium the mean concentration (by volume) in rats was only 23% of that in the gaseous phase. Metabolism proceeded very slowly and was saturable at exposure concentrations of about 260 mg/m Its maximum rate was 1% that of vinyl chloride and less than 20% that of vinyl fluoride there has been a report of an increase in the urinary excretion of fluoride in exposed rats. No alkylating intermediate was demonstrated after passage through a mouse-liver microsomal system. However, vinylidene fluoride inhibits mixed-function oxidase activity in vitro and, like similar halogenated compounds that are transformed to reactive metabolites, it alters rat intermediary metabolism, leading to acetone exhalation (lARC, 1986). 

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

Pharmacokinetic properties Meptazinol has poor oral bioavailability due to extensive first-pass metabolism. Systemic availability is improved after rectal administration. Peak plasma concentrations are reached 30 min after rectal or intramuscular administration and plasma half-life is about 2 h. Plasma protein binding is low ( 30%). Meptazinole is extensively metabolized in the gut and liver mainly to the glucuronide derivative. Only about 10% is excreted unmetabolised in the faeces (Franklin, 1988). 

---