Antipyrine elimination

Antipyrine from 300 ml solutions containing 0.6, 6, or 60pM was readily taken up by mussels. Within 40-80 minutes an apparent steady state was achieved. Uptake experiments were routinely conducted for 120 minutes (Figure 1). An analogous antipyrine elimination curve is shown in the lower portion of the figure. 

Ginkgo extract has no effect on the hepatic microsomal drug oxidation system, as measured by antipyrine elimination, even at doses of 400 mg per day (Duche et al. 1989). Ginkgo metabolites, the substituted benzoic acids (4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, hippuric acid and 3-methoxy-4-hydroxybenzoic acid [vanillic acid]), are excreted in urine (Pietta et al. 1997). 

Chambers DM, Jefferson GC, Chambers M, Loudon NB. Antipyrine elimination in saliva after low-dose combined or progestogen-only oral contraceptive steroids. Br J Clin Pharmacol 1982 13(2) 229-32. 

Wensing, G., Ohnhaus, E.E. Hoensch, H.P. (1990) Antipyrine elimination and hepatic microsomal enzyme activity in patients with liver disease. Clinical Pharmacology and Therapeutics, 47, 698-705. 

Uptake and Elimination. Six mussels were placed into 600 ml beakers containing 300 ml aerated Instant 0ceanR (10-12°C) for a 1/2 hr acclimation period before addition of antipyrine (3 pCi/ beaker) (or other test compound). Aliquots (1.0 ml) were taken at intervals and placed directly into scintillation fluid (10 ml, 3a70B, Research Products International Corp., Elk Grove Village,... 

IL). Initial experiments showed that uptake was complete within 2 hours. At the end of 2 hours (uptake) the mussels were rinsed, antipyrine solution was replaced with fresh Instant 0ceanR, and sampling at intervals continued. Portions of the water were also analyzed for antipyrine and metabolites. Data expressed in counts per minute per 1.0 ml were used to represent uptake and elimination of antipyrine. Experiments were routinely done in triplicate. 

Graphs relating antipyrine concentrations and time were used to calculate clearance rates. A relationship between apparent antipyrine steady state concentrations at 120 and 240 minutes (api 2 o, ap2 o) and mussel body water and mantle cavity water was also determined (k). Mantle cavity water is that volume held between the valves when the mussels are closed, e.g., when transferred from the uptake solution (300 ml) to the elimination solution (300 ml). The initial antipyrine concentration (apo) was determined at the beginning of the experiment. Assuming no loss of antipyrine, complete mixing of the solutions, and its distribution into total mussel body water, when an apparent steady state is achieved, the following results ... 

Quantitative estimation of ventilation by indirect methods in mussels requires four assumptions (16) a) reduction of concentration results from uptake, b) constant ventilation (pumping) rate, c) uptake of a constant percentage of concentration (first order process), d) homogeneity of the test solution at all times. Our transport studies have utilized antipy-rine (22, 23) a water soluble, stable chemical of low acute toxicity to mussels. It is readily dissolved in ocean water or Instant Ocean and is neither adsorbed nor volatilized from the 300 ml test system. Mussels pump throughout the 4 hour test period and this action is apparently sufficient to insure homogeneity of the solution. Inspection of early uptake and elimination curves (antipyrine concentration as a function of time) prompted use of Coughlan s equation (16) for water transport. 

Figure 1. Antipyrine uptake and elimination data taken from 3 experiments. Six mussels in 300 mL Instant Ocean were used in each. The 1 mL aliquots were taken at the end of each interval.

Mussels held at 11°C in aerated Instant Ocean. Antipyrine (6 ViM 1.65 mCi/mmole) in 300 ml. One ml aliquots taken at zero, 120 (uptake), and 240 (elimination) min. Three beakers per set. 

Antipyrine uptake and elimination half-Jives were measured in both Pacific Ocean water and Instant Ocean. Measurements were made immediately after collection of the mussels (0 day). 

The uptake and elimination half-lives of 176 and 169 min and 27 and 29 min were similar to each other and to half-lives obtained using mussels maintained in the laboratory. Half-lives in the longer term laboratory culture experiments (Table IV) were similar to each other. Similarly, the mantle cavity and body water constants gave no indication of stress (Table II). Mussels used in these experiments were selected by size (ca. 6 g viscera fresh weight) and variability could be reduced by adoption of more objective criteria. Instant Ocean culture does not directly effect antipyrine disposition and laboratory conditions are suitable for maintenance of animals for at least short times. 

Antipyrine uptake and elimination was also assessed in the presence of aldrin and p-nitroanisole, among substrates used in biotransformation studies (Table V). Altered antipyrine half-lives might indicate that the levels of the substrates were stressful to the mussels. The levels used did not overtly effect the mussels pumping activity, and half-lives were within the range of control values. Antipyrine disposition measurements will be included in studies on the biological fate of chemicals. 

Antipyrine Uptake and Elimination by Mussels Directly Removed or Laboratory Cultured. 

Effect of Aldrin, p-Nitroanisole, and SKF 525A on Uptake and Elimination of Antipyrine by Mussels... 

Estimated from linear portion of uptake and elimination curves (semilog). Six mussels per 300 ml containing 1.8 ymole antipyrine (0.6 pM). 

Antipyrine metabolism in vivo has also been demonstrated. Following extraction of media from uptake and elimination studies, TLC analysis revealed the parent compound and 4-hydroxy-antipyrine. Based upon the amount of radioactivity recovered, the metabolite may account for up to 4% of the total. This hy-droxylated metabolite is the primary oxidation product in animals studied to date (23). Further characterization of the extracts using high-pressure liquid chromatography will be done in the future. 

Similar considerations can also be made for animals of different gender. Antipyrine plasma elimination, for example, in rats and cattle show gender differences that, to some extent, cannot be mediated by sex hormones. In contrast, clearance of antipyrine and sulfamethazine in female dwarf goats markedly decreases following implantation of the anabolic steroid trenbolone (64). 

In the rat, development to adult levels of activity takes about 30 days after which levels decline toward old age. In humans, however, hydroxylase activity increases up to the age of 6 years, reaching levels greater than those in the adult, which only decrease after sexual maturation. Thus the elimination of antipyrine and theophylline was found to be greater in children than in adults. It should be noted, however, that proportions of isoenzymes may be very different in neonates from the adult animal, and the development of the isoenzymes may be different. Thus, in the rat there seem to be four types of development for phase 1 metabolizing enzymes linear increase from birth to adulthood, type A (aniline 4-hydroxylation) low levels until weaning, then an increase to adult levels, type B (N-demethylation) rapid development after birth followed by rapid decline to low levels in adulthood, type C (hydroxylation of 4-methylcoumarin) and rapid increase after birth to a maximum and then decline to adult levels, type D. Patterns of development may be different between sexes as well as between species. For example, in the rat, steroid 16-a-hydroxylase activity toward androst-4-ene-3,17-dione develops in type B fashion in both males and females, but in females, activity starts to disappear at 30 days of age and is undetectable by 40 days. It seems that the monooxygenase system develops largely as a unit, with the rate dependent on species and sex of the animal and the particular substrate. 

The active metabolite 4-methyl-amino-antipyrine reaches peak plasma concentrations 1.2 to 2 h after oral administration and is further metabolised with a mean elimination half-life of 2.6 to 3.5 h. Of the four main metabolites about 60% are excreted in the urine. Protein binding of these metabolites is less than 60% (Levy et al. 1995). 

FIGURE 7.4 Relationship between Child-Pugh stages of liver disease severity and extent of impairment in antipyrine breath test (ABT), galactose elimination capacity (GEC), sorbitol clearance, and indocyanine green clearance (ICG). (Adapted from data published by Herold C, Heinz R, Niedobitek G et al. Liver 2001 21 260-5.)... 

Antipyrine is oxidized through biotransformation, independently of perfusion, predominantly in the micro-somes, and is excreted after hydroxylation and conjugation. After oral administration (15 or 18 mg/kg BW, respectively), the metabolic clearance ability of the liver (metabolic capacity of the microsomal monooxygenase system) can be assessed by computation of the concentration curve and the plasma half-life (after 3 and 24 hours). The serum half-life and plasma clearance are significantly enhanced/decreased, depending on the reduction in liver function. There is a close correlation with the galactose elimination capacity as well as with Quick s value. (58-60, 74, 88)... 

The metabolism of gasoline is not known, although it is expected that the interaction of the various components of gasoline may affect the metabolic products that are formed. The interaction of the components of gasoline is likely to influence the metabolizing enzymes such that the elimination rate of a compound may be altered (NESCAUM 1989). The increased metabolism of antipyrine... 

In a study of the disposition of antipyrine (20 mg/kg, i.v.) in eight healthy Standardbred mares aged between six and nine years, the following values (mean + SD or median (range)) were obtained for the major pharmacokinetic parameters Pd(ss) (mL/kg) 864 (731-952), CZb (mL/minkg) 6.2 (4.3-8.6), MRT (h) 2.3 (1.7-3.5), and the overall elimination rate constant (per hour) 0.37 + 0.09 (Dyke et al, 1998). It was established that renal clearance accounts for < 2% of systemic clearance, which implies that hepatic clearance exceeds 98%, and that 4-hydroxyantipyrine (formed by hepatic microsomal oxidation) is the major... 

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