Glucuronides, toxic

Lotsch J, Zimmermann M, Darimont J, et al Does the Al 18G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity Anesthesiology 97 814-819, 2002... 

Accumulation of morphine-6-glucuronide is a risk factor for opioid toxicity during morphine treatment. However, it does not occur in all patients with renal insufficiency, which is the most common reason for accumulation of morphine-6-glucuronide this suggests that other risk factors can contribute to morphine-6-glucuronide toxicity. 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

Similar to 5-FU, there is a polymorphism associated with irinotecan toxicity. UDP-glucuronosyltransferase (UGT1A1) is an enzyme responsible for the glucuronidation of SN-38 to inactive metabolites, and reduced or deficient levels of this enzyme correlate with irinotecan-induced diarrhea and neutropenia.39 Recently the FDA approved a blood test that detects variations in this gene. This test will assist health care providers in predicting which patients may develop severe toxicities from normal doses of irinotecan and can be ordered prior to patients receiving irinotecan. binotecan is administered as an IV bolus over 60 to 90 minutes in a variety dosing schedules. 

The activity of glucuronidation is low in the newborn, especially in premature babies (6). This is evident in the jaundice observed in many newborns because the major clearance pathway for bilirubin is glucuronidation. This can also lead to increased toxicity of some drugs in the newborn such as the grey baby syndrome seen in newborns treated with chloramphenicol. 

Lech, J. J., Statham, C. N. Role of glucuronide formation in the selective toxicity of 3-trifluoromethyl-4-nitrophenol (TFM) for the sea lamprey comparative aspects of TFM uptake and conjugation in sea lamprey and rainbow trout. Toxicol. Appl. Pharmacol. (1975), 37(1) 150-158. 

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. 

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