Drug Hyperbilirubinemia

Host factors can help to ensure selection of the most appropriate antimicrobial agent. Age is an important factor in antimicrobial selection. With regard to dose and interval, renal and hepatic function varies with age. Populations with diminished renal function include neonates and the elderly. Hepatic function in the neonate is not fully developed, and drugs that are metabolized or eliminated by this route may produce adverse effects. For example, sulfonamides and ceftriaxone may compete with bilirubin for binding sites and may result in hyperbilirubinemia and kernicterus. Gastric acidity also depends on... 

Drugs that should not be combined due to overlapping toxi-cities include amprenavir oral solution plus ritonavir oral solution, atazanavir plus indinavir (due to enhanced hyperbilirubinemia), and any combination of didanosine, stavudine, and zalcitabine. Emtricitabine and lamivudine should not be combined because of their similar chemical structures, and antagonism can result when lamivudine is combined with zalcitabine, or stavudine is combined with zidovudine. 

As far as sinusoidal uptake is concerned, drug-drug interactions have also been reported between antituberculosis agents (rifamycin SV and rifampicin) and bromosulfophthalein in humans both drugs reduce the clearance of bromosul-fophthalein and also induce hyperbilirubinemia [108]. These results may be ac-... 

Drug interaction with proton pump inhibitors, unconjugated hyperbilirubinemia Twice daily dosing lipids Twice-daily dosing lipids... 

Campbell, S.D., de Morais, S.M. and Xu, J.J. (2004) Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chemico-Biological Interactions, 150, 179-187. 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other Pis, occurring in 3-5% of patients. There have also been rare cases of acute hemolytic anemia. 

Unauthorized use of these diuretics, or the failure to follow label indications for approved use in the cattle, could lead to unacceptable residues in meat and milk destined for human consumption. While there are no official tolerances for these drugs in milk, the Food and Drug Administration (FDA) has established safe levels that range from 7 ppb for trichlormethiazide, to 10 ppb for furosemide, and 67 ppb for the other thiazides (56). Administration of diuretics is associated with potential toxic effects such as bone marrow depression, hyperbilirubinemia. 

Some patients receiving indinavir exhibit nephrolithiasis/urolithiasis including flank pain that may be accompanied by hematuria. The frequency of nephrolithiasis is dependent on the period of treatment with indinavir. Other side effects associated with indinavir include insulin resistance, hyperglycemia, asymptomatic hyperbilirubinemia, HIV lipodystrophy syndrome and skin abnormalities. Indinavir should not be coadministered with drugs that affect the cytochrome P-450 system (CYP3A4). Antacids are not recommended within 2 h of its administration, specifically didano-sine containing an antacid buffer. 

Rh-negative mothers with prior exposure to Rh-positive infants Hemolysis Infection Dehydration Breast-feeding Hypothryoidism Maternal drug use Drugs given to infants Familial nonhemolytic hyperbilirubinemia... 

One needs to keep in mind that the use of drugs by the mother will sometimes lead to impairment of the activity of bilirubin-UDP-glucuronyltransferase. Phenothiazines are an example of this kind of interaction. The use of drugs in the neonatal intensive care unit also can contribute to hyperbilirubinemia. Usually, the medications that compete for binding sites on albumin are the culprits in this case (see section on Bilburin Transport). An example of this type of interaction is the use of furosimide, which is a diuretic used to decrease fluid retention and improve cardiac function and renal output. 

Sulfonamides are extensively protein bound. If these drugs are administered to mothers immediately before delivery or to the premature or full-term infant while there is physiologic hyperbilirubinemia, they may displace bilirubin from plasma protein, causing severe jaundice or kemicterus (8). 

These include postnatal depression and acute dystonic reactions (which may interfere with normal delivery). Hypotonia can persist for months (569) and may respond to diphenhydramine 5 mg/kg/day. Severe rhinorrhea and respiratory distress in a neonate exposed to fluphenazine hydrochloride prenatally has been reported (484). Neonatal jaundice, hyperbilirubinemia, and melanin deposits in the eyes have occurred when neuroleptic drugs were given during the last trimester or longer during pregnancy. 

Also. -naphthylisothiocyanate (ANIT) enhances the measured HO activity. ANIT is a drug causing bile stasis, hyperbilirubinemia acutely, bile duct hyperplasia and biliary cirrhosis (Leonard et al. (1981), Ushida et al. (2002)). Therefore its HO activity enhancing potential is well known. 

---