Zidovudine metabolism

Eight subjects took zidovudine for 3 days with and without probenecid 500 mg every 8 hours for 3 days, and then additional quinine sulfate 260 mg every 8 hours (47). Probenecid increased the AUC of zidovudine by 80%. Quinine prevented the probenecid effect but had no effect on zidovudine kinetics when it was taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal ehmination of zidovudine. 

Komhauser DM, Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG, Lietman PS. Probenecid and zidovudine metabolism. Lancet 1989 2(8661) 473-5. 

Drug interactions Drugs that undergo hepatic glucuronidation, including acetaminophen, benzodiazepines, cimetidine, and sulfonamides, may increase plasma levels of zidovudine. Metabolism of zidovudine may also be inhibited by azole antifungals and by protease inhibitors. Rifampin increases the clearance of zidovudine. 

Not understood. Paracetamol does not increase the serum levels of zidovudine, which might have provided an explanation for the apparent increased toxicity. One in vitro study found that paracetamol does not affect the glucuronidation ofzidovudine, whereas another found that paracetamol did inhibit zidovudine metabolism to the glucuronide. The effeet of zidovudine on paraeetamol metabolism is also unclear. 

SteffeEM, Kii JHjInciardi JF,FtynnNF, GoldsteinE, TaijesTS, BenetLZ. The effect of acetaminc hen on zidovudine metabolism in HIV-infected patients. J Acqmr Irmnune D c Syndr( 990) 3,691. ... 

Two NtRTIs, zidovudine and stavudine, antagonize each other s metabolism and should not be given together. 

TMPase acts to dephosphorylate both TMP and its precursor dUMP, forming a mixture of TdR and 2 -deoxyuridine (UdR). As a starting material for zidovudine synthesis, TdR must be essentially free of this impurity, which would pass through the manufacturing process to form a demethylated analogue of zidovudine. Separation of TdR and UdR requires difficult and costly downstream processing hence, the key to a commercial process is metabolic engineering to minimize biosynthetic UdR. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Hepatic function impairment- Because zidovudine is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients. Frequent monitoring for hematologic toxicities is advised. 

Aduits- Following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Zidovudine is primarily eliminated by hepatic metabolism. 

Renal/Hepatic function impairment Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). In patients with severely impaired renal function (Ccr less than 15 mL/min), dosage reduction is recommended. Although very little data are available, patients with severely impaired hepatic function may be at greater risk of toxicity. 

A fatal interaction between ritonavir and MDMA (methylenedioxymethamphetamine, ecstasy) has been reported in an HIV-positive man (see Henry et ah, 1998). The patient had allegedly taken MDMA on several occasions without untoward effects. However, several weeks after ritonavir was added to his regular medication with zidovudine and lamivudine, he took some MDMA for recreational purposes and died of a cardiorespiratory arrest within hours. Toxicology showed that the plasma MDMA concentration was about ten times that expected from the ingested dose. Inhibition of CYP2D6, the principal pathway for MDMA metabolism, by ritonavir was thought to be the most likely cause. 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

Stavudine possesses several clinically significant interactions with other drugs. Although hydroxyurea enhances the antiviral activity of stavudine and didanosine, combination therapy that includes stavudine and didanosine, with or without hydroxyurea, increases the risk of pancreatitis. Combinations of stavudine and didanosine should not be given to pregnant women because of the increased risk of metabolic acidosis. Zidovudine inhibits the phosphorylation of stavudine thus, this combination should be avoided. 

A. Diazepam is metabolized in the liver by CYP3A4 and CYP2C19 efavirenz inhibits both of these isozymes and is likely to increase plasma levels of diazepam. Diazepam is almost completely converted to inactive metabolites therefore, renal elimination is not much of a concern. Lamivudine may produce fatigue as a side effect but does not potentiate the depressant activity of diazepam. Zidovudine does not induce cytochrome P450 activity, and diazepam does not have to be converted to an active form for sedative activity. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

J, Vazquez G. Fat distribution and metabolic abnormalities in HIV-infected patients on first combination antiretroviral therapy including stavudine or zidovudine role of physical activity as a protective factor. Antivir Ther 2003 8 223-31. 

Besides being affected by medications and substances that affect the liver s metabolism, methadone itself affects the liver s metabolism of certain substances. A significant number of people who are taking methadone for heroin addiction also are HIV positive and are taking anti-HIV medications such as Desipramine (DMI) and zidovudine (AZT). Through its actions on the liver, methadone decreases the metabolism of these medications. Because of this, certain troublesome side effects of DMI and AZT, including nausea,... 

A number of currently prescribed NRTIs are shown in Figure A.44. Compounds A.155 through A.158 are all analogues of pyrimidine nucleosides. Compounds A.159 and A.160 are both purine nucleoside analogues. Abacavir (Ziagen, A.160) is inactive until it is metabolized to carbovir (A.161) in vivo. The seven drugs in Figure A.44 were approved in the United States over a span of more than 25 years. Zidovudine reached the market first in 1987, and emtricitabine was the last to be approved in 2003. The steady release... 

VALPROATE ANTIVIRALS-ZIDOVUDINE t zidovudine levels Inhibition of metabolism Watch for early features of toxicity of zidovudine... 

PROBENECID ZIDOVUDINE t levels of zidovudine with cases of toxicity i hepatic metabolism of zidovudine Avoid co-administration if possible if not possible, l dose of zidovudine... 

It is instructive to examine which drugs are substrates for various isoforms of CYP enzymes. Table 11.2 lists some of the substrates for different CYP isoforms (10, 11). There are several examples of a single compound that is metabolized by multiple CYP enzymes (acetaminophen, diazepam, caffeine, halothane, warfarin, testosterone, zidovudine), and CYP enzymes that metabolize bioactive endogenous molecules (prostaglandins, steroids) as well as drugs. 

The pharmacokinetic parameters for zidovudine in various age groups are presented in Table 23.2 (4-7). Newborns cleared zidovudine more slowly than did children and adults, and the clearance in preterm newborns is slower than in the full-term infants. Zidovudine clearance rapidly increases over the first few weeks of life, consistent with the up-regulation of glucuronidation pathways in newborns after birth, and by 2 weeks of age approaches values in older children and adults. In addition, the extent of zidovudine absorption (F) in newborns at 14 days of age is higher than in older children, presumably because of reduced first-pass metabolism. Based on these studies, a safe and potentially effective dose of zidovudine was defined for term and preterm newborns (6-8). 

---