Coordination-number dependence of magnetic hyperfine fields at (111)Cd on Ni surfaces.

Ferromagnetic Ni surfaces were investigated on an atomic scale using the perturbed angular correlation spectroscopy probe (111)Cd. A comprehensive set of data for magnetic hyperfine fields (B(hf)) at various probe sites is presented. A field variation from -7 T in Ni bulk to the surprisingly large value of 16 T at the adatom position on Ni(111) is observed. A continuous nonlinear dependence is found, correlating the experimental B(hf) values with the number of their nearest Ni neighbors. The data are discussed on the basis of recent calculations on B(hf) values at sp-element impurities on ferromagnetic surfaces.

Effect of rifampin, phenobarbital pretreatment, and acetylator phenotype on acetylisoniazid metabolism in the rabbit.

The metabolism of [14C]acetylisoniazid was studied in male New Zealand White rabbits. Pretreatment of the rabbits with the microsomal enzyme inducers rifampin and phenobarbital had little effect on acetylisoniazid metabolism. Rifampin appears to produce some inhibition of acetylation of the metabolite acetylhydrazine to diacetylhydrazine. Acetylation phenotype was an important factor. Covalent binding of 14C to hepatic protein increased as the acetylation rate decreased. In plasma and urine acetylhydrazine levels were negatively correlated with acetylation rate and diacetylhydrazine levels were positively correlated as one would expect. It was concluded that in the rabbit covalent binding to hepatic protein was more dependent on the acetylation rate than on induction of microsomal oxidase.

Metabolism of [14C]acetylisoniazid and [14C]acetylhydrazine by the rat and rabbit.

Male rats and rabbits were singly dosed with either 1-[14C]acetyl isoniazid (acetylisonicotinoylhydrazine, acetyl-INH, 200 mg/kg po) or 1-[14C]acetylhydrazine (50 or 100 mg/kg ip). Urine and expired 14CO2 were collected, and after 6 hr the animals were killed for the analysis of tissue 14C concentrations and covalent binding of 14C to hepatic protein. Rats excreted proportionately more 14C in urine and had lower 14C levels in their tissues compared to rabbits. When acetyl-INH was administered, covalent hepatic protein binding of the acetyl moiety was greater in the rabbit than the rat, but the opposite was observed when acetylhydrazine was administered. Analysis of blood and urine by TLC revealed that the rabbit more rapidly metabolized both acetyl-INH to acetylhydrazine, and acetylhydrazine to diacetylhydrazine than did the rat. These observations suggest that higher amidase activity in the rabbit compared to the rat leads to faster conversion of acetyl-INH to acetylhydrazine which in turn leads to greater covalent binding and hepatotoxicity.

Isoniazid metabolism in the rabbit, and the effect of rifampin pretreatment.

The metabolism of 14C-isonicotinyl hydrazide (INH) (50 mg/kg, po) was studied in male New Zealand White rabbits and the effect on INH metabolism of pretreating the rabbits for 7 days with rifampin (100 mg/kg po per day) was also studied. The 14C-labelled metabolites were separated and quantitated by TLC and the unlabelled hydrazino metabolites by GLC. Absorption and elimination of INH was rapid since the peak blood 14C level was attained by 1 hr and the T 1/2 of elimination was 2.67 +/- 0.36 hr. By 12 hr 68.5 +/- 4.1% of the dose was recovered in the urine. The major metabolite excreted in the urine was isonicotinic acid (INA) which accounted for 40.3 +/- 3.5% of the dose followed by acetylisoniazid (AcINH) at 15.8 +/- 1.2%. The relatively high proportion of INA excreted by the rabbit compared to the rat and human is attributed to a high level of amidase in the rabbit, and is suggested as a possible explanation for the rabbit's sensitivity to INH-induced hepatotoxicity. Rifampin pretreatment produced only one significant change in the parameters studied and that was a reduction in AcINH excreted in urine. It is suggested that this effect may be due to rifampin increasing hepatic amidase activity.

Effect of analgesic nephropathy in women on the metabolism and excretion of 14C-acetaminophen.

Nephropathy due to excessive consumption of phenacetin-containing analgesic mixtures has been a problem in Canada. Following the withdrawal of phenacetin it seems probable that acetaminophen consumption will increase and this study investigated the metabolism of 14C-Acetaminophen in patients with nephropathy and in healthy women. The respective alpha T1/2s of excretion of Acetaminophen and its metabolites were 2.58 h in the controls, 4.28 h in patients with analgesic nephropathy and 6.53 h in patients with nephropathy due to causes other than analgesic abuse. Both groups of patients had T1/2s that were significantly longer than the controls. The total 12 h recovery of 14C was highly positively correlated with creatinine clearance. (R = 0.92, P less than 0.001). No significant shifts in metabolism were discernable. It is concluded that patients with either analgesic nephropathy or nephropathy due to other causes metabolise Acetaminophen normally but excretion is delayed in proportion to the degree of renal impairment.

Failure to observe pathology in the rat following chronic dosing with acetaminophen and acetylsalicylic acid.

Male Wistar rats were dosed daily by gavage for 200 days with either (1) aspirin, 200 mg/kg; (2) acetaminophen, 200 mg/kg; (3) aspirin and acetaminophen, 200 mg/kg of each; (4) aspirin and acetaminophen, 100 mg/kg of each or (5) vehicle alone. None of the treatments produced any marked signs of toxicity and no drug related deaths were observed. The full dose combination (3) did significantly reduce the weight compared to the control group (5). When urinary lactic dehydrogenase and alkaline phosphatase were measured, all treatments caused some increase in activity but those containing aspirin had the greatest effect. Urinary pH and osmolarity were not effected by the treatments. Complete pathological examination of the animals failed to detect any significant changes when compared to the controls. It is concluded that there is no evidence of a toxic interaction between aspirin and acetaminophen in the rat.

Effect of subacute dosing and phenobarbital and 3-methylcholanthrene pretreatment on the metabolism of acetaminophen in rats.

The metabolism of 14C-ring-labelled acetaminophen was studied in male Wistar rats. Pretreatment with phenobarbital increased the initial rate of elimination of 14C from the blood and increased the amount of acetaminophen glucuronide excreted in the urine. Pretreatment with 3-methylcholanthrene did not significantly affect the rate of elimination from the blood and decreased the amount of acetaminophen glucuronide in the urine. Daily dosing with acetaminophen for up to 3 weeks increased the rate of elimination of 14C from the blood after 4 h, and increased the urinary excretion of both total 14C and the glucuronide and sulfate conjugates. Subacute dosing with acetaminophen had a diuretic effect but this did not correlate with the increased excretion of the drug. It is concluded that acetaminophen elimination is increased by phenobarbital pretreatment and by subacute dosing with acetaminophen, but by different mechanisms.