Hepatic function /metabolism / toxicity

Mexifitene is well absorbed from the GI tract and less than 10% undergoes first-pass hepatic metabolism. In plasma, 60—70% of the dmg is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.5—2.0 lg/mL. The plasma half-life of mexifitene is 10—12 h in patients having normal renal and hepatic function. Toxic effects are noted at plasma concentrations of 1.5—3.0 lg/mL, although side effects have been noted at therapeutic concentrations. The metabolite, /V-methy1mexi1itene, has some antiarrhythmic activity. About 85% of the dmg is metabolized to inactive metabolites. The kidneys excrete about 10% of the dmg unchanged, the rest as metabolites. Excretion can also occur in the bile and in breast milk (1,2). 

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. 

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. 

Pharmacokinetics Because of its severe toxicity to the Gl tract, 5-FU is given intravenously or, in the case of skin cancer, topically. The drug penetrates well into all tissues including the CNS. 5-FU is metabolized in the liver, largely to CO2, which is expired. The dose must be adjusted in the case of impaired hepatic function. 

Asparaginase and vincristine should not be used together on the same day, since simultaneous administration can cause increased vincristine toxicity. It has been suggested that this is due to a deleterious effect of asparaginase on hepatic function, reducing the metabolism of vincristine (5). 

In the previous sections, a number of chemicals that cause acute toxic liver injury have been reviewed in relation to their biochemical actions with or without tryptophan administration. It is of special interest that tryptophan was able to improve hepatic protein metabolism when administered before, simultaneously, or after administering the toxic compound (Table 6.2). Likewise, the effects of tryptophan on altered liver function due to the acute administration of selected drugs are reviewed. Overall, the experimental findings demonstrate that many of the regulatory effects of tryptophan on hepatic protein metabolism can occur even during acute liver injury. This raises many questions as to whether L-tryptophan may possibly have therapeutic applications under certain states of liver injury. Further experimental studies should establish whether this consideration is valid or not. 

Xenon is extremely insoluble in blood and other tissues, providing for rapid induction and emergence from anesthesia (Table 13-1). It is sufficiently potent to produce surgical anesthesia when administered with 30% oxygen. Most importantly, xenon has minimal side effects. It has no effects on cardiac output or cardiac rhythm and is not thought to have a significant effect on systemic vascular resistance. It also does not affect pulmonary function and is not known to have any hepatic or renal toxicity. Finally, xenon is not metabolized in the human body. Xenon is an anesthetic that may be available in the future if the limitations of availability and cost can be overcome. 

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning.20... 

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