Zidovudine glucuronidation

Abbreviations ZDV, zidovudine AUC, area under concentration-time curve CL, clearance CLf, formation clearance AUC(m), AUC of the metabolite AUCp, AUC of parent Ae, amount excreted unchanged in urine Ae(ml, amount of metabolite excreted in urine ZDV-G, zidovudine glucuronide. 

Zidovudine glucuronidation in human hepatic micro-somes in vitro was inhibited more by the combination of fluconazole with valproic acid than with other drngs, snch as atovaquone and methadone (117). 

In 13 HIV-infected patients with cancer, the mean pharmacokinetics of zidovudine (AUC, half-life, oral clearance, and oral apparent volume of distribution) were no different with or without chemotherapy (42). However, there was a 57% reduction in and a 66% increase in tmax after chemotherapy. There were no differences in the urinary excretion of zidovudine or zidovudine glucuronide. The authors concluded that these minor changes did not warrant any change in the dosage of zidovudine during concurrent chemotherapy. 

GaUicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A, Kwok D, Foster BC, Cameron DW. Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Chn Pharmacol 1999 48(2) 168-79. 

Nadal, T. Ortuno, J. Pascual, J.A. Rapid and sensitive determination of zidovudine and zidovudine glucuronide in human plasma by ion-pair high-performance liquid chromatography. J.C/tromotogr.A, 1996, 721, 127-137... 

Kamali, R Rawlins, M.D. Simple and rapid assay for zidovudine and zidovudine glucuronide in plasma using high-performance liquid chromatography. J.Chromatogr., 1990, 530, 474-479... 

In vitro data suggest that the altered zidovudine pharmacokinetics may, in part, occur because fluconazole inhibits zidovudine glucuronidation. ... 

Kamali F, Rawlins MD. Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro. Biopharm Drug Dispos (1992) 13, 403-9. 

Experimental clinical evidence indicates that probenecid reduces metabolism (glucuronidation) of zidovudine by the liver enzymes, and inhibits renal secretion of the zidovudine glucuronide metabolite. " " The interaction with zalcitabine is presumably due to inhibition of zalcitabine secretion in the renal tubules. ... 

Campion JJ, Bawdon RE, Baskin LB, Barton Q. Effect of probenecid on the pharmacokinetics of zidovudine and zidovudine glucuronide. Pharmaco erapy (1990) 10,235. 

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. 

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. 

Zidovudine-j8-d- rat plasma glucuronide Enantiomers of Drugs and Related Compounds deproteination... 

The serum half-life averages 1 hour, and the intracellular half-life of the phosphorylated compound is 3.3 hours. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency. 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (zidovudine) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and val-proic acid. Antimicrob Agents Chemother 1998 42 1592-1596. 

ATOVAQUONE ANTIVIRALS-ZIDOVUDINE Atovaquone t zidovudine levels Atovaquone inhibits the glucuronidation of zidovudine Uncertain clinical significance. Monitor FBC, LFTs and lactate closely during co-administration... 

Zidovudine is a synthetic nucleoside analog that blocks replication of the human immunodeficiency virus (HIV) by inhibiting reverse transcriptase. The primary indication for zidovudine administration in newborns is the prevention of vertical transmission of HIV. Like chloramphenicol, zidovudine is eliminated in adults primarily by glucuronide conjugation, suggesting that newborns may have a reduced capacity to eliminate zidovudine. However, unlike... 

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). 

Lee BL, Tauber MG, Sadler B, Goldstein D, Chambers HE. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996 59(1) 14-21. 

Concomitant administration of paracetamol and zidovudine leads to inhibition of glucuronidation and to potentiation of the toxicity of each drug (131,132). 

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