Metabolism by Drugs

Problems of combining cimetidine with hypertension drugs were soon apparent. In 1981, ranitidine (Zantac, 8.91), another H2-receptor antagonist, reached the market. Ranitidine also inhibits metabolism, but only CYP2D6. Isoform 2D6 is less crucial in the metabolism of common drugs. Ranitidine took much market share from cimetidine because of cimetidine s relatively large number of drug interactions. 

Hyperforin has been shown to increase the activity of CYP3 A4 and CYP2C9 by binding nuclear receptors that regulate gene expression of certain CYP-encoding genes.18 As a result, St. John s Wort can have the opposite effect as cimetidine. Patients who take St. John s Wort in conjunction with their prescribed medicines may find that their 

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In lipid metabolism, there is elegant balance in the levels of end-product lipids, and the enzymes and genes involved in their biosynthesis, as well as close cooperation with other metabolisms to maintain homeostasis. When the balance is lost, obesity or hyperlipidemia will develop, leading to a variety of serious diseases including atherosclerosis, hypertension, diabetes, functional depression of certain organs, and so on. Therefore, the control of lipid metabolism by drugs could lead to the prevention or treatment of these diseases. 

The export of phospholipids and cholesterol can be simultaneous owing to the activity of various members of the ABC superfamily (see Table 18-2). The best-understood example of this phenomenon is in the formation of bile, an aqueous fluid containing phospholipids, cholesterol, and bile acids, which are derived from cholesterol. After export from liver cells, phospholipids, cholesterol, and bile acids form water-soluble micelles in the bile, which is delivered through ducts to the gallbladder, where it is stored and concentrated. In response to a fat-containing meal, bile is released into the small intestine to help emulsify dietary lipids and thus aid in their digestion and absorption into the body. As we shall see later, the alteration of biliary metabolism by drugs can be used to prevent heart attacks. 

This generally describes the process of drug absorption into the body, distribution throughout the body, metabolism by degrad a tive and metabolizing enzymes in the body, and finally elimination from the body. It is useful to consider each of these steps because together they summarize pharmacokinetics. 

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

Antidiabetic Drugs other than Insulin. Figure 3 The antihyperglycaemic effect of metformin involves enhanced insulin-mediated suppression of hepatic glucose production and muscle glucose uptake. Metformin also exerts non-insulin-dependent effects on these tissues, including reduced fatty acid oxidation and increased anaerobic glucose metabolism by the intestine. FA, fatty acid f, increase i decrease. 

In vitro studies in human liver fractions indicated that azacitidine may be metabolized by the liver. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

It is important to monitor closely serum blood levels of chloramphenicol, particularly in patients with impaired liver or kidney function or when administering chloramphenicol with other drugs metabolized by the liver. Blood concentration levels exceeding 25 mcg/mL increase the risk of the patient developing bone marrow depression. 

Many drugs when administered to humans can result in a marked increase in ALASl. Most of these drugs are metabolized by a system in the liver that utilizes a specific hemoprotein, cytochrome P450 (see Chapter 53). During their metabolism, the utilization of heme by cytochrome P450 is greatly increased, which in turn diminishes the intracellular heme concentration. This latter event effects a derepression of ALASl with a corresponding increased rate of heme synthesis to meet the needs of the cells. 

The major mono oxygenases in the endoplasmic reticulum are cytochrome P450s—so named because the enzyme was discovered when it was noted that preparations of microsomes that had been chemically reduced and then exposed to carbon monoxide exhibited a distinct peak at 450 nm. Among reasons that this enzyme is important is the fact that approximately 50% of the drugs humans ingest are metabolized by isoforms of cytochrome P450 these enzymes also act on various carcinogens and pollutants. 

Figure 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

Many gold compounds have been tested for their potential antitumor activity by examining their cytotoxicity against cell lines in culture. This avoids barriers that arise in vivo due to uncertain absorption, restricted distribution, and variable metabolism of drugs. 

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