Effect of H2 antagonists on the differential secretion of triamterene and its sulfate conjugate metabolite by the isolated perfused rat kidney.

The isolated perfused rat kidney model was used to examine the effect of the histamine H2 antagonists cimetidine, ranitidine, and famotidine and the organic anion inhibitor probenecid on the differential renal handling of triamterene and its active metabolite p-hydroxytriamterene sulfate. The kidneys were perfused with a Krebs-Henseleit buffer containing albumin, glucose, and amino acids to pH 7.4, and drug concentrations were measured by HPLC. At an initial triamterene concentration of 0.5 mg/liter, the unbound renal clearance to glomerular filtration rate (GFR) ratio was 11.0 +/- 2.5 (mean +/- SD): 1, indicating substantial tubular secretion of the drug. Cimetidine and ranitidine reduced the tubular secretion by about 80% (p less than 0.01), famotidine by between 35 and 60% (p = 0.05), whereas probenecid had no inhibitory effect. For p-hydroxytriamterene sulfate, its unbound renal clearance to GFR ratio was 41 +/- 25:1; this was not affected by cimetidine, ranitidine, or famotidine, whereas probenecid significantly (p less than 0.01) reduced the rate of tubular secretion by 80%. These data indicate that the renal tubular secretion of triamterene is mediated by the organic cation system, whereas for p-hydroxytriamterene sulfate its tubular secretion is via the organic anion system. Famotidine is a weaker inhibitor of the organic cation system compared with cimetidine and ranitidine. These results have implications for drug-drug interaction studies involving renal elimination pathways.

Deconjugation of p-hydroxytriamterene sulphate in the rat.

1. The extent of deconjugation of p-hydroxytriamterene sulphate was studied in rats, by h.p.l.c., after i.v., i.p., and oral administration. 2. After i.v. administration, deconjugation accounted for 29-54% of the recovered dose as free p-hydroxytriamterene in urine and faeces. Following i.p. administration, 70-88% was deconjugated and 72-96% was deconjugated after oral administration. Most of the p-hydroxytriamterene was recovered in faeces.

Renal tubular secretion of amiloride and its inhibition by cimetidine in humans and in an animal model.

The histamine H2 antagonist cimetidine has been shown to reduce the renal tubular secretion of other organic cations through competition for the specific transport system with organic cations in the renal proximal tubule. The potential interaction between cimetidine and the potassium-sparing diuretic amiloride was investigated in humans and in the isolated perfused rat kidney. A chronic dosing study was conducted in eight healthy subjects who received, in random order, amiloride (5 mg daily), cimetidine (400 mg twice daily), both drugs together, and a control phase in which no drug was present. Cimetidine reduced the renal clearance of amiloride by a mean of 17%, from 358 +/- 134 to 299 +/- 118 ml/min (p less than 0.05), and the urinary excretion of amiloride from 65 +/- 11 to 53 +/- 13% of the dose (p less than 0.05). Amiloride reduced the excretion of cimetidine from 43 +/- 7 to 32 +/- 9% of the dose (p less than 0.05) and the area under the plasma concentration-time curve for cimetidine by a mean of 14% (p less than 0.05) but had no effect on the renal clearance of cimetidine. In the perfused rat kidney, cimetidine reduced the amiloride unbound renal clearance to glomerular filtration rate ratio from 5-7:1 to 1-2:1 (p less than 0.05). These studies demonstrate that cimetidine inhibits the renal tubular secretion of amiloride in humans and in rats to a similar extent. In addition, in humans the gastrointestinal absorption of both amiloride and cimetidine appear to be reduced by each other, by an as yet unknown mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene.

A chronic-dosing pharmacokinetic study was carried out in six healthy subjects to examine the potential for cimetidine to reduce the CLR and CLH of triamterene. Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine significantly reduced the clearance of triamterene by hydroxylation by 32% (P less than 0.016) and the CLR of triamterene by 28% (P less than 0.063), with no change in its protein binding. The CLR of the active sulfate conjugate of triamterene was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine, suggesting a decreased absorption. These results are consistent with cimetidine inhibiting cytochrome P-450 enzymes in the liver and also competing with triamterene for renal tubular secretion. Despite the pharmacokinetic interaction, cimetidine caused minimal alteration to the natriuretic and antikaliuretic effects of triamterene.

Epidemiology and control of vaginal discharges in the sow after service.

A syndrome associated with vaginal discharge, endometritis and reproductive inefficiency in the served sow is described. In some herds pregnancy failures exceeded 15 per cent with increased returns to service and sows not in pig. Predisposing factors included the age of the herd and the hygiene and management practices from weaning to service and during the 21 days after service. No one organism was implicated but venereal transmission was considered possible. One hundred and ten breeding herds were surveyed and in 26 of these control measures were necessary. These included antibacterial therapy of the prepuce of the boar and medication of the sow from weaning until 21 days after service. Such treatment together with management changes resolved the problem in 22 of the herds. The syndrome reappeared in four out of seven herds where treatment of the boar was not continued.

The pig advisory visit in preventive medicine.

An approach to advisory work on intensive pig units is described. Detailed methods of carrying out an advisory visit include the clinical examination discussions and record evaluations, special topic presentations and the report. Check lists are presented for use in different parts of the production system and a suggested preventive medicine programme for a 250-sow herd is described. The economics of the service show a cost factor of only 0.17 per cent of gross turnover and guides to the veterinary time are given.