Time-dependent uptake and metallothionein-binding of gold, copper and zinc in the rat kidney.

In rats, in which the whole body burden of Au decreases rapidly, but biphasically, maximum kidney concns are not attained until 10-15 days after a single intraperitoneal dose of either Au(I) or Au(III). The concn of metallothionein-bound Au and of total kidney Cu, which also increases after the administration of the Au compounds, however, reach maxima at 5 days. Between at least 6 and 24 hr after Au treatment, the increases in the concn of Au and Cu in the metallothionein fraction are highly correlated. Measurements on the kidneys of animals at early times (15 min-6 hr) after dosing with Au(III) indicate that the Zn content of the (endogenous) metallothionein is depressed during the first hour, shows a transient increase at 2 hr and then falls to a minimum at 6 hr. Subsequent (6-24 hr) changes in metallothionein-bound Zn parallel those of metallothionein-bound Au and Cu. It seems, therefore, that Au and Cu are incorporated simultaneously into rat kidney metallothionein and this incorporation may be mediated by an initial displacement of Zn. In rats exposed to five doses of Au(III) the half-times of total and metallothionein-bound Au in the kidneys are appreciably longer than those in animals given a single dose. In both groups, the concns of Cu and Zn in the renal metallothionein do not decrease in parallel with that of Au, but change roughly in proportion to their whole kidney concns. In consequence, the metal composition of the metallothionein fraction, which remains above the endogenous concn in the normal kidney throughout an experimental period of 90-140 days, alters considerably with time.

The effects of cadmium and copper on the renal uptake and metallothionein binding of gold in the rat and hamster.

Rats and hamsters, (pre)-treated with copper and cadmium, were used to investigate whether species-differences in renal metallothionein synthesis in response to gold were determined by changes in the kidney concentrations of other metals. The effects of both dietary copper limitation and excess on the renal metabolism of gold also were studied in the rat. In this species, all of the pre-treatments affected the renal concentrations of total and metallothionein-bound copper, but none of them altered either the kidney uptake or thionein-binding of gold. Incorporation of zinc into the metallothionein, which accompanied the binding of gold in this fraction of the kidney, however, was influenced slightly by the pretreatments, In hamsters, pretreatment with cadmium, which increased the concentrations of total and thionein-bound zinc in the kidneys, also did not affect the renal uptake of gold, although it increased significantly the binding of gold to the metallothionein fraction of the renal cytosol. This increased binding of gold also was accompanied by further increases in the zinc and copper contents of the metallothionein; the contents of total and thionein-bound cadmium, however, remained essentially unchanged. Concentrations of copper and zinc in the hamster kidney were not affected significantly by subcutaneous administration of copper alone (five daily doses, each of 3.2 mg Cu/kg body wt.), but were increased when gold was given during the copper-treatment. The concentrations of gold, copper and zinc in the renal metallothionein fraction also were increased under these conditions. From these results it seems that kidney metallothionein synthesis in response to gold may be related to the changes in either the concentration or distribution of zinc, rather than copper.

Comparative studies on the distribution of gold, copper and zinc in the livers and kidneys of rats and hamsters after treatment with sodium [195Au]-aurothiomalate.

The distribution of gold, copper and zinc in the livers and kidneys of female rats and hamsters was determined after intraperitoneal injection of sodium [195Au]-aurothiomalate. After five doses of sodium [195Au]-aurothiomalate (1 mg Au(I) per kg body weight), the hepatic and renal concentrations of Au were greater in rats than in hamsters. In the former species, treatment with the Au(I)-compound led to an increase in the Cu-concentration of the kidney and to the synthesis of a (Cu, Au)-metallothionein. In either species binding of Au to the hepatic metallothionein was insignificant. The renal (Cu, Au)-metallothionein from the sodium [195Au]-aurothiomalate-treated rat appeared to be extremely heterogeneous and was resolved into at least four components on ion exchange chromatography.

The tissue distribution of gold, copper and zinc in animals treated with Au (III); species differences in the binding of these metals in the kidney.

Whole body retention of Au and the distribution of Au, Cu and Zn have been measured in female rats, rabbits, guinea-pigs, hamsters and mice after either a single injection or multiple doses of Au(III). At 24 h after a single intraperitoneal injection whole body retention of Au was about 65% of the dose in the rabbit and 50% of the dose in other species. After five doses, retention (as a percentage of the total dose) ranged from 36% in mice to 49% in rats. Concentrations of Au in the kidneys were lowest in mice and highest in rats but, in all species, were greater than in other organs. In rats and guinea-pigs, but not in hamsters, rabbits and mice, treatment with Au(III) increased the Cu content of the kidneys and of the soluble fraction isolated therefrom. The latter from the rat and guinea-pig kidney contained both Au and Cu in association with a low molecular weight metalloprotein (metallothionein), which also contained Zn and was separated by ion exchange chromatography into three subspecies. Binding of Au by these metalloproteins appeared to be related to the renal accumulation of Cu. Apart from the mouse, in which renal accumulation of Au was low, slight damage resulted in the kidneys of all species after treatment with Au. It appears, therefore, that nephrotoxicity cannot be explained simply by the renal concentration of Au and the form in which it is accumulated within the tubular cells.

Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

The efficacy of two bupivacaine hydrochloride injection products.

OBJECTIVE: The relative efficacy of two bupivacaine hydrochloride injection products was investigated in patients who were undergoing intra-ocular eye surgery. DESIGN: Patients took part in this double-blind, randomised, parallel-group study and received either Macaine (Keatings) or Regibloc (Intramed), according to the randomisation schedule. SETTING: The study was carried out in the ophthalmology operating theatres of National and Pelonomi Hospitals, Bloemfontein, South Africa. PATIENTS: Thirty male and 74 female patients who needed extra-capsular lens extraction plus intra-ocular lens implantation, extra-capsular lens extraction, or trabeculectomy were selected for the study. OUTCOME MEASURES: Akinesia was evaluated after 10, 15 and 20 minutes. In the event of incomplete akinesia after 20 minutes, an additional injection was administered, and after 5 minutes another evaluation of akinesia was done. Anaesthesia was evaluated at the beginning of surgery. RESULTS: The proportions of patients who received no additional anaesthesia were 57.7% for Macaine and 70.8% for Regibloc (difference 13.1%, 95% confidence interval (CI) -5.5 - 31.7%). The proportions of patients with adequate akinesia (possibly after additional anaesthesia) were 90.4% for Macaine and 89.6% for Regibloc (difference -0.8%, 95% CI-12.6 - 11.0%). The proportions of patients experiencing no pain or discomfort at the beginning of surgery were 88.2% for Macaine and 87.5% for Reglibloc (difference -0.7%, 95% CI-13.6 - 12.1%). CONCLUSION: The study results indicate that Regibloc is at least as effective as, or superior to, Macaine in achieving adequate akinesia.

Relative bioavailability of four clomipramine hydrochloride tablet products.

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2 x 25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 2 x 25 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5 x 10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 5 x 10 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable Cmax were 31.3 ng mL-1 for the reference and 31.6 ng mL-1 for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL-1 and 753 ng h mL-1 for the reference and test, respectively. In study 2, the geometric mean Cmax values were 25.8 ng mL-1 and 23.9 ng mL-1 for the reference and test respectively; the geometric mean AUC values were 569 ng h mL-1 and 547 ng h mL-1. The 90% confidence intervals for the 'test/reference' mean ratios of the plasma clomipramine pharmacokinetic variables Cmax and AUC(0-infinity) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80-125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.