Systemic considerations renal system

As shown in Figure 2-4, there is a considerable body of data on the health effects of carbon tetrachloride in humans, especially following acute oral or inhalation exposures. Although many of the available reports lack quantitative information on exposure levels, the data are sufficient to derive approximate values for safe exposure levels. There is limited information on the effects of intermediate or chronic inhalation exposure in the workplace, but there are essentially no data on longer-term oral exposure of humans to carbon tetrachloride, most toxicity studies have focuses on the main systemic effects of obvious clinical significance (hepatotoxicity, renal toxicity, central nervous system depression). There are data on the effects of carbon tetrachloride on the immune system, but there are no reports that establish whether or not developmental, reproductive, genotoxic, or carcinogenic effects occur in humans exposed to carbon tetrachloride. 

Labetalol is almost completely absorbed from the gastrointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gastrointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circulation. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates. The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essentially unchanged in patients with impaired renal failure. 

The parent CDs as GRAS food additives are suitable for oral pharmaceutical use when used at the levels approved for foods. The GRAS estimated daily mean oral exposures for P-CD, a-CD, and y-CD were reported as 300, 1700, and 4000mg/day, respectively. These levels provide reasonable quantities for consideration in oral pharmaceutical products. As stated earlier, the parent CDs, however, are not suited for intravenous (TV) use due to the early reports of their renal toxicity, and this limitation led researchers to introduce chemical modifications to provide new, system-ically safe CDs for use in parenteral pharmaceuticals. 

Because Cd accumulation in bones is considerably lower that concentrations found in liver and kidney, it was initially hypothesized that that skeletal effects were secondary to renal toxicity. This notion is still reported in several texts. A number of rodent studies have been conducted that clearly demonstrate Cd-induced skeletal effects at lower concentrations and/or at shorter exposure durations than is needed to induce renal toxicity. Many in vivo studies involve measuring the rates of 45Ca mobilization trombone. Calcium naturally is released trombones as they are remodeled. Remodeling is the process by which bone is broken down and rebuilt in order to optimize structure and architecture. Approximately 7-8% of the skeletal system (by mass) is remodeled annually. Calcium is mobilized as small packets of bone are released. In experiments with rodents, 45Ca was released trombones nearly twice as quickly as control animals after 10 days of dietary Cd exposure at 50ppm. This Ca release preceded renal toxicity symptoms. Similar studies showed increased 45Ca release from both dog and mice as early as three days post Cd exposure via the diet. 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

The presence of systemic disease can alter the way an individual detoxifies or excretes a drug. Liver and kidney disease, in particular, can markedly influence drug response by allowing the drug to accumulate to toxic levels. The rate of excretion of digoxin, for example, is reduced considerably in patients with renal impairment, thus causing an increased risk of alterations in color vision in these patients. 

B. Azole antifungals include systemic agents such as keto-conazole, fluconazole, itraconazole, and voriconazole. Topical agents used for the treatment of vaginal candidiasis and thrush include miconazole and clotrimazole. The pharmacologic properties of the systemic azoles differ considerably. Ketoconazole, the first oral azole developed, has poor bioavailability and requires an acidic environment for enhanced absorption. Thus, initial studies required ketoconazole to be administered with a cola to increase bioavailability. Fluconazole, unlike itraconazole and ketoconazole, is hydrophillic and has increased penetration across the blood-brain barrier. Fluconazole is also the only azole that is renally eliminated. 

Renal excretion mechanisms appear to mature within the first 2 weeks after birth in foals, calves, lambs, kids and piglets, while their maturation in puppies may take 4-6 weeks. In a study of the pharmacokinetics of amikacin in critically ill full-term foals ranging in age from 2 to 12 days, the systemic clearance of the aminoglycoside was lower (indicating impaired renal function) and the half-life was considerably prolonged in uraemic compared with non-uraemic foals (Adland-Davenport et al., 1990). 

The presence of a renal dopamine paracrine-autocrine system explains the considerable amounts of free dopamine excreted in the urine. Most derives from renal uptake and decarboxylation of circulating L-dopa and reflects the plasma levels of this amino acid and the function of the renal dopamine paracrine-autocrine system. 

The first caveat is that all clearance pathways (hepatic, renal, biliary or other) must be taken into consideration. If a compound undergoes a high level of hepatic clearance, then in vitro-in vivo scaling may be used to predict the fraction of systemic clearance expected from this pathway. If a compound undergoes a high level of renal elimination, allometric scaling may be also used to predict the clearance attributed to this pathway. 

---