Antipyrine metabolite kinetics have been investigated in the rat with respect to dose and time dependence. The metabolic pathways, 4-hydroxylation, benzylic oxidation, and N-demethylation, are of equal quantitative importance (approximately 20 per cent of dose) and show no dose dependence over the range 25-500 mg kg-1. By using [N-methyl-14C]-antipyrine, the single carbon fragment lost by N-demethylation may be monitored as 14CO2. Serial sampling of 14CO2 exhalation rate provides a half-life estimate which, according to theoretical principles, reflects the antipyrine plasma half-life. When both half-lives were measured in the same animals a statistically significant correlation was evident. At doses of 250 mg kg-1 and 500 mg kg-1 there is an increase in CER half-life (218 and 303 min respectively) when compared to a dose below 100 mg kg-1 (152 min). The metabolite formation rate constants are decreased accordingly at the high doses but are invariant over the dose range 25-100 mg kg-1. Although inter-rat variation in antipyrine metabolite kinetics was substantial, intra-rat variability was small. The noninvasive nature of determining antipyrine metabolite kinetics via breath and urine analysis provides a potentially useful animal model system to investigate the factors influencing hepatic mixed function oxidase activity in vivo.

Animals↗

PubMedDate not supplied

Specialist registration.

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Humans↗

PubMedDate not supplied

Multiple regression of predictors and criteria of dental school performance.

This study reports normative data for 370 students admitted to the UCLA School of Dentistry, data on commonly used performance predictors, and the regression equation best fitted for forecasting performance in this school. Most variance was associated with denatl school grade point average, National Board Dental Examination averages, and clinical performance. Best predictors were achievement level and trend in preadmission academic performance. The selection interview and high school preformance were also evaluated as predictor criteria.

Age Factors↗

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Quantitation of extrahepatic metabolism. Pulmonary and intestinal conjugation of naphthol.

There is much evidence in the literature to indicate extrahepatic conjugation of naphthol by various isolated tissue preparations. Using in vivo methodology, where multiple sites of input are employed, it has been demonstrated that both lung and intestinal mucosa make a significant contribution in the conjugation of naphthol in the rat. Under the conditions studied, both of the above organs (pulmonary extraction ratio 0.44, intestinal extraction ratio 0.46) are more than twice as effective as the liver in eliminating naphthol (hepatic extraction ratio 0.18). This multiple sites of input method has been compared with a multiple sites of sampling method. Similar results have been obtained in quantifying pulmonary conjugation of naphthol. The relevant merits of the two approaches are discussed.

Animals↗

PubMedDate not supplied

Inhibition of antipyrine metabolite formation. Steady state studies with cimetidine and metyrapone in rats.

Antipyrine metabolite kinetics have been characterized in rats receiving an intravenous infusion of either saline, cimetidine, or metyrapone. 14CO2 exhalation rate-time profiles following [N-methyl-14C] antipyrine administration demonstrate that, when either cimetidine or metyrapone is maintained at a steady state plasma concentration, a constant degree of inhibition is evident. Under the conditions imposed in this in vivo study, the inhibitory potency of metyrapone is approximately 6 times that observed with cimetidine. Rate constants for the formation of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine have been calculated using breath and urinary metabolite data under the steady state inhibitory states. Metyrapone nonselectively inhibits the formation of all three oxidative metabolites by approximately one-third. Cimetidine inhibition is selective where rates of 3-methyl-hydroxylation and N-demethylation are reduced by 50% yet 4-hydroxylation is unaffected. The value of assessing inhibitory responses under steady state conditions is discussed and the nonlinear nature of the kinetics of inhibition, when a single bolus dose of inhibitor is used, is illustrated by means of computer simulation.

Animals↗

PubMedDate not supplied

Plasma concentration-response relationship for cimetidine inhibition of drug metabolism in the rat.

Cimetidine inhibition of antipyrine elimination has been studied in the rat over a range of steady state cimetidine concentrations. Cimetidine is a potent inhibitor of antipyrine metabolism with a concentration of about 1.25 mg/liter causing a 50% decrease in the total plasma clearance of antipyrine. The degree of inhibition of antipyrine clearance caused by cimetidine is dependent upon its plasma concentration, but the relationship is not linear. The formation clearances of all antipyrine metabolites measured--3-hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine--are inhibited by cimetidine at all concentrations used. The susceptibility of the different metabolites to cimetidine inhibition does vary. The renal clearance of antipyrine was also decreased by cimetidine by an unknown mechanism. Analysis of the individual formation clearances suggests that the inhibition of oxidative metabolism due to cimetidine is caused by its binding to two classes of enzyme sites--a high affinity, low capacity and a low affinity, high capacity site. These two different sites would appear to be responsible for the production of different metabolites of antipyrine. The true nature of the selectivity of cimetidine inhibition of antipyrine metabolism is apparent from the formation clearances but not from the urinary metabolite patterns.

Animals↗

PubMedDate not supplied

Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine.

The glucuronidation of morphine, naloxone, and buprenorphine by the liver and intestine has been assessed both in vitro and in vivo in the rat. Using microsomes, Vmax/Km ratios were estimated as measures of intrinsic enzyme activity, and a wide range of ratios were obtained (500-fold). The ratio for the intestine was consistently less than for the liver, and the rank order of activities within each tissue was morphine less than naloxone less than buprenorphine. Using various routes of administration, plasma concentration-time profiles for each compound were determined and used to estimate hepatic and intestinal extraction ratios. These extraction ratios were dose-independent and more substantial for the liver than the intestine. For each tissue, buprenorphine and naloxone showed similar extraction, whereas morphine was less. Plasma binding and blood/plasma concentration ratios were determined, and perfusion models were used to calculate intrinsic clearance. This in vivo parameter of enzyme activity showed a wide range (200-fold), comparable to the spread of microsomal Vmax/Km ratios. Although the in vivo parameters consistently gave measures 10- to 30-fold higher than the in vitro parameters, the rank order was identical for the two sets. These data suggest that a comparative approach to correlate in vitro and in vivo data has advantages over the use of absolute drug characteristics.

Animals↗

PubMedDate not supplied

Aminopyrine demethylation kinetics. Use of metabolite exhalation rates as an index of enhanced mixed-function oxidase activity in vivo.

The usefulness of determining aminopyrine demethylation kinetics via monitoring of metabolite exhalation rats had been assessed. In rats receiving [N-dimethyl-14C]aminopyrine, a biexponential decline in the 14CO2 exhalation rate is apparent when monitoring is continued over a 5 to 6-hr period. Both the fast phase (representing the first demethylation) and the slower phase (representing the second demethylation) are markedly influenced by phenobarbital and promethazine pretreatment. These changes are consistent with enhanced mixed-function oxidase activity. Examination of the urinary excretion products of aminopyrine obtained in these studies support this claim. The sensitivity of the above index of mixed-function oxidase activity is increased considerably by the use of crossover experimental designs. Considerable interanimal variation is observed in the metabolite production in both exhaled air and urine from rats administered aminopyrine.

Aminopyrine↗

PubMedDate not supplied

Antipyrine metabolite kinetics in phenobarbital and beta-naphthoflavone-induced rats.

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Animals↗

PubMedDate not supplied

In vivo capacity of hepatic and extrahepatic enzymes to conjugate phenol.

Phenol has a high metabolic clearance in the rat and shows extensive first pass metabolism. The ability of the intestinal mucosa, liver, and lung to conjugate phenol is investigated over a 35-fold dose range by employing a judicious choice of route of administration. Comparison of blood phenol concentration-time profiles, following intravenous administration into the jugular and the hepatic portal veins, indicates extensive hepatic conjugation of phenol at low doses. However, the capacity of the hepatic enzymes is readily saturated. This observation is confirmed in isolated perfused livers. Comparison of blood phenol concentration time profiles, following vascular administration into the carotid artery and the jugular vein, indicates substantial pulmonary conjugation of phenol. Although the extent of pulmonary conjugation is less than the hepatic contribution, it is evident over a wider dose range than the latter organ. Intestinal conjugation of phenol is assessed by comparison of data from intraduodenal and hepatic portal venous administration. At low doses of phenol (less than 1 mg/kg), intestinal and hepatic conjugation are comparable. The capacity of the intestinal conjugating enzymes is remarkably high; at large doses (greater than 5 mg/kg), intestinal conjugation far exceeds the contribution of the hepatic and pulmonary enzymes.

Animals↗