By glucuronidation

The active metabolite of this drug is mycophenolic acid (MPA), which inhibits IMPDH, too. MPA is metabolized in vivo by glucuronidation. It has to be noted that its acyl glucuronide inhibits EVDPDH with similar potency compared to the parent compound. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by microsomal oxidation followed by glucuronide conjugation. 

Fig. 7.26 Structure of morphine, which is metabolized to a more active opioid analgesic by glucuronidation at the 6 position.

Metabolism - The major routes of metabolism are hydroxylation followed by glucuronide conjugation. 

Metabolism - Nalmefene is metabolized by the liver, primarily by glucuronide conjugation, and excreted in the urine less than 5% is excreted in the urine unchanged, and 17% is excreted in the feces. 

Does not include agents metabolized by glucuronidation (lorazepam, oxazepam, temazepam). 

Dihydroartemisinin (DHA) is the active metabolite of acetalic derivatives of artemisinin (artemether, artesunate). Oxidation by cytochrome P450 enzymes or/and hydrolysis provides DHA, which is itself poorly stable in vivo. Indeed, the corresponding oxonium ion, a precursor of inactive metabolites by ring opening or by glucuronidation, can easily be formed (Figure 4.15). 

Lamotrigine is metabolized by glucuronidation, possibly by the UGT 1A4 system. As such, it is vulnerable to other UGT inducers—oral contraceptives, phenytoin, carbamazepine, phenobarbital and primidone, and to a UGT inhibitor, valproate (Hachad et ah, 2002). 

It is inactive orally because of high first pass metabolism in liver. Metabolised by glucuronidation in liver. The main use of naloxone is in the treatment of acute opioid overdose (acute morphine poisoning). It also precipitates withdrawal syndrome when administered to morphine addicts. The constricted pupils of addicts dilate after administration of naloxone. This has been used as a diagnostic tool for opioid addiction. 

The absorption is rapid with maximum plasma concentration being attained 30 to 40 minutes after oral administration. Highly plasma protein bound and metabolised by glucuronidation. 60% is excreted unchanged in urine. 

BZDs biotransformed by hepatic oxidation have relatively long half-lives and usually have active metabolites ( Table 12-10). Those biotransformed by glucuronide conjugation have relatively short half-lives and no active metabolites. Only a few BZDs (e.g., clonazepam) are biotransformed by nitro reduction. Although oxidized BZDs and their metabolites may be more likely to accumulate due to age, liver disease, or concomitant use of estrogens or cimetidine, clinical data substantiating this theory are incomplete. 

Most drugs used in anaesthesia are metabolised in the liver by phase I reactions, mediated by cytochrome P-450 enzymes. These are susceptible to destruction by cirrhosis, so that the biotransformation of drugs, such as opioids (except morphine), benzodiazepines, barbiturates, and inhalational agents, may be markedly altered in severe liver disease. These enzymes are found in the centrilobular areas, which are more prone to hypoxia. In contrast, the enzymes responsible for phase II reactions, found predominantly in the peripheral areas, often function normally even in advanced disease. The disposition of benzodiazepines that are eliminated primarily by glucuronidation, e.g. lorazepam and oxazepam, are unaffected by chronic liver disease. For drugs with low hepatic extraction, advanced hepatocytic dysfunction decreases phase I and II biotransformation with a reduced clearance and prolongation of the elimination half-life. This is often partially offset by an increased free fraction due to decreased protein binding. 

Diclofenac undergoes hepatic methylation and oxidation, creating (6 metabolites that are all susceptible to conjugation by glucuronidation and sulfation. A major metabolite of diclofenac is considered to be its hydroxylated derivative,... 

Peak plasma concentration after oral application occurs within 2 h. Ketoprofen is bound to plasma protein up to 99% and shows a plasma elimination half-life of 1.5 to 4 h. It is metabolized mainly by glucuronidation and excreted mainly in the urine (Jamali and Brooks, 1990). 

The peak plasma concentration of oral ketorolac is reached within 30 to 60 min and may be slower after intramuscular administration. It is bound to plasma proteins by more than 99%. The terminal plasma half-life is about 4 to 6 h and is prolonged in elderly and in patients with renal dysfunction. Ketorolac is metabolized mainly by glucuronidation and to a minor extent by para-hydroxylation and is excreted in the urine ( 90%) and faeces ( 10%) (Buckley and Brogden, 1990). 

Pharmacokinetic properties Codeine (Sindrup and Brosen, 1995) has a good oral bioavailability. The compound is extensively metabolized by O- and N-demethylation followed by glucuronidation. The main metabolites are norcodeine, morphine and hydrocodeine and their glucuronides. There are indications (Yue et al., 1997), that the analgesic effect is reduced in persons with low CYP2D6 activity (poor metabolizers). 

Pharmacokinetic properties Due to intensive first-pass metabolism, nalbuphine has a low oral bioavailability of less than 10%. After intramuscular administration peak plasma concentrations are reached after 30 min, half-life time is about 5 h. The compound is metabolized by glucuronidation and to a minor extent by N-dealkylation, and less than 10% is excreted unmetabolized (Lo et al., 1987). 

Pharmacokinetic properties Oral naloxone is extensively metabolized in the gut and liver, predominantly by glucuronidation of the phenol function (Berkowitz, 1976). 

Pharmacokinetic properties Pentazocine is orally bioavailable but there is a high degree of fluctuation in resorption. The compound is rapidly and extensively metabolized. Metabolites are formed by oxidative demethylation of the methyl residues of the dimethylallyl group and by glucuronidation (Berkowitz, 1973). The metabolic pathway of pentazocine is shown in scheme 42. 

After oral administration, abacavir is rapidly absorbed, and its bioavailability is about 83%. Food does not interfere with its absorption, and it is metabolized by alcohol dehydrogenase to 5 -carboxylic acid derivative and to S -glucuronidc by glucuronidation. Abacavir does not affect the cytochrome P-450 system. In combination with other antiretroviral drugs, abacavir is indicated for the treatment of HIV-1 infection. It is more potent than other nucleoside reverse transcriptase inhibitors in reducing HIV plasma concentration and increasing CD4+ count. 

Oral contraceptives increase the plasma clearance of clofibric acid, which is mainly metabolized by glucuronidation (341,342). 

Morphine is known to be metabolized by glucuronidation to two biologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (Boemer et al., 1975). M6G has high affinity for the /(-opioid receptor (Loser et al., 1996 Pasternak et al., 1987 Paul et al., 1989) and appears to be a more potent opioid agonist than morphine (Frances et al., 1992 Osborne el al., 2000 Pasternak et al., 1987 Paul el al., 1989). In contrast, M3G does not bind to ji-, 6-, or K-opioid receptors (Loser et al., 1996 Pasternak et al., 1987) and appears to be devoid of analgesic activity (Pasternak et al., 1987 Yaksh and Harty, 1988). 

Zheng Y et al (2007) Elimination of antiestrogenic effects of active tamoxifen metabolites by glucuronidation. Drug Metab Dispos 35 1942-1948... 

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