Effect of cationic drugs on the renal secretion of ranitidine in the rat isolated perfused kidney.

1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [3H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400-700 ng/mL. The renal clearance of ranitidine (CL[R]) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [14C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n = 4 in each case) were administered to achieve low, medium and high concentrations during the 20-40, 40-60 and 60-80 min periods, respectively. 4. The mean (+/- SD) unbound fraction of ranitidine in the perfusion medium was 0.889 +/- 0.046 and was not altered (P>0.05) by the presence of the other drugs. 5. The CL(R)/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion. 6. The CL(R)/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL(R)/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.

Disposition of morphine in the rat isolated perfused kidney: concentration ranging studies.

The rat isolated perfused kidney was used to investigate the linearity of the renal disposition of morphine and its potential oxidative and glucuronidative metabolism by the kidney. In a set of single-dose experiments, morphine was administered to recirculating perfusion medium to achieve initial concentrations of 0.2, 2 and 20 microM (n = 4 at each concentration). In a set of multiple-dose experiments, morphine was administered to perfusate as sequential bolus doses to achieve concentrations of 0.2, 2, 20 and 200 microM (n = 6). HPLC was used to determine the concentration of morphine in perfusate and urine. Normorphine, morphine-3-glucuronide and morphine-6-glucuronide could not be detected in perfusate or urine, a result that suggests an absence of oxidative and glucuronidative metabolism of morphine by the rat kidney. The volume of distribution of morphine within the kidney was high (31 +/- 3 ml/g at 0.2 microM), which indicates extensive accumulation, and remained constant with increasing perfusate concentration. The ratio of unbound renal excretory clearance to glomerular filtration rate was always greater than unity for all kidneys, which indicates that the renal excretion of morphine involves net tubular secretion. This ratio was constant (P > .05) over the 100-fold concentration range of the single-dose study. In the multiple-dose study, the ratio was marginally but significantly (P < .05) higher at concentrations of 2, 20 and 200 microM than at 0.2 microM, a difference that cannot be explained by saturation of tubular secretion. The results suggest that the tubular secretion of morphine is not saturated over a wide range of concentrations (0.2-200 microM).

Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver.

Acyl glucuronides are reactive electrophilic metabolites and in vivo are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to proteins. The isolated perfused liver preparation, using male Sprague-Dawley rats, was used to examine the hepatic disposition of the fibrate hypolipidemic agent gemfibrozil and its acyl glucuronide metabolite, 1-O-gemfibrozil-beta-D-glucuronide. Using a recirculating design, erythrocyte-free perfusion medium containing 1% (w/v) albumin was delivered to the liver via the portal vein at a flow rate of 30 ml/min, and for each experiment was spiked with either gemfibrozil (N = 4) or 1-O-gemfibrozil-beta-D-glucuronide (N = 4) at initial concentrations of 120 microM and 21 microM, respectively. In the gemfibrozil perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio of gemfibrozil, and the fraction of eliminated gemfibrozil excreted in bile as the glucuronide conjugate were 2.73 (0.30) ml/min, 76.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. In the 1-O-gemfibrozil-beta-D-glucuronide perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio, and fraction excreted in bile as the glucuronide conjugate were 19.5 (2.1) ml/min, 8.7 (0.9) min, 0.649 (0.068), and 0.534 (0.077), respectively. The higher hepatic extraction ratio for 1-O-gemfibrozil-beta-D-glucuronide could mostly be attributed to its higher unbound fraction in perfusate (0.182), compared with that of the parent drug (0.004), because the conjugate had a lower intrinsic clearance (305 ml/min) compared with the aglycone (751 ml/min). Control perfusions, conducted in the absence of a liver, showed negligible degradation of 1-O-gemfibrozil-beta-D-glucuronide over 90 min. However, in the presence of a liver, approximately 25% of 1-O-gemfibrozil-beta-D-glucuronide added to perfusate was hydrolyzed to gemfibrozil over 90 min. The study demonstrates the importance of the liver in the formation, uptake, hydrolysis, and excretion of 1-O-gemfibrozil-beta-D-glucuronide.

Comparison of one or two weeks of lansoprazole, amoxicillin, and clarithromycin in the treatment of Helicobacter pylori.

BACKGROUND: The simplest, most effective, and least expensive Helicobacter pylori therapy remains to be determined. Two weeks of 30 mg lansoprazole bid, 1 gm amoxicillin bid, and 500 mg clarithromycin bid (LAC2) had been shown to be an effective therapy for H. pylori. The aim of this study was to assess whether 1 week of this regimen (LAC1) would have a similar efficacy. MATERIALS AND METHODS: H. pylori-positive patients assessed histologically, by rapid urease test, microbiologically, and by a 13C-urea breath test (13C-UBT) were randomized to receive either LAC1 or LAC2 in a single-center open study. Patients were interviewed 1 to 3 days after completion of therapy to evaluate adverse events and compliance. Efficacy was determined by 13C-UBT at least 4 weeks after antibiotic therapy. RESULTS: Seventy evaluable patients were randomized to receive LAC1 (n = 33) LAC2 (n = 37). Of the 33 LAC1 patients, 30 (91%) were treated successfully (95% confidence interval (CI) = 76-98%), compared with 32 of 37 (86%) in the LAC2 group (95% CI = 71-96%). There was no difference in efficacy between the two groups (Fisher's exact test p = 1.0; 95% CI = -10.3%-19.2%). Patients taking LAC1 experienced significantly fewer severe adverse events than those taking LAC2 (Mann-Whitney U test). One of 64 patients had primary resistance to clarithromycin, and treatment was unsuccessful in this case. Six of the 7 remaining treatment failures developed secondary resistance to clarithromycin. CONCLUSIONS: LAC1 is as effective as LAC2 and is associated with less toxicity. Posttreatment clarithromycin resistance is common in patients who do not experience success with therapy.

Disposition of L-carnitine and acetyl-L-carnitine in the isolated perfused rat kidney.

The isolated perfused rat kidney was used to investigate the regulation, specificity and concentration-dependence of the renal tubular disposition of L-carnitine (LC) and its ester, acetyl-L-carnitine (ALC). Tritiated markers were used to study the renal disposition of LC and ALC and HPLC was used to purify 3H-LC and 3H-ALC before radiochemical analysis. At perfusate concentrations comparable to those found in plasma in vivo (50 microM for LC and 5 microM for ALC), the renal clearance of both analogues was substantially less than GFR (P < .05) which, in view of their negligible binding to perfusate proteins, is indicative of extensive reabsorption. During the first 20 min of perfusion, the percent tubular reabsorption (%TR) of LC and ALC was 94 +/- (SD) 2.6% and 97 +/- 0.6%, respectively. The extent of 3H-ALC and 3H-LC enrichment of perfusate in experiments with 3H-LC and 3H-ALC, respectively, provided evidence for the capability of the rat kidney to acetylate LC and deacetylate ALC. In addition, a portion of renally generated 3H-ALC and 3H-LC was found to undergo leakage into renal tubules and escape subsequent reabsorption. It was also found that the %TR of both compounds decreased substantially when the perfusate concentration was increased above endogenous levels; each compound was capable of decreasing the %TR of the other; and trimethylamine-N-oxide, a metabolite of LC, had no significant effect on the renal handling of the carnitine derivatives.

The disposition of morphine and its metabolites in the in-situ rat isolated perfused liver.

A specific HPLC method with UV detection was used to investigate the disposition of morphine and its metabolites in the in-situ rat isolated perfused liver preparation. Livers of male Sprague-Dawley rats (n = 4) were perfused under single pass conditions with protein- and erythrocyte-free perfusate, containing 2.66 microM morphine, for up to 90 min. The concentration of morphine, normorphine and morphine-3-glucuronide (M3G) in outflow perfusate, and the biliary excretion of M3G and normorphine glucuronide, all reached steady-state levels within 15-20 min after commencing perfusion. At steady-state, the mean (+/- s.d.) extraction ratio of morphine was 0.87 +/- 0.06 and clearance (26.0 +/- 1.7 mL min-1) approached perfusate flow rate (30 mL min-1). Although M3G was the main metabolite, accounting for 72.8 +/- 12.7% of eliminated morphine, a significant proportion (21.6 +/- 13.5%) was N-demethylated to normorphine and was recovered as unchanged normorphine in outflow perfusate and normorphine glucuronide in bile. The biliary extraction ratio of hepatically-formed M3G was 0.61 +/- 0.31. Results from an additional six experiments, in which livers were perfused with 1.33 and 2.66 microM of morphine for 30 min each in a balanced cross-over manner, indicated that the disposition of morphine and its metabolites was approximately linear within this concentration range.

The Children's Depression Rating Scale for normal and depressed outpatients.

The Children's Depression Rating Scale (CDRS) was devised by Poznanski, Cook, and Carroll in 1979, to diagnose depression in 6- to 12-year-olds. The authors state a score of 30 indicates significant depression, with scores in the 20 to 30 range indicating borderline depression. Normative outpatient data for the CDRS have not, however, been established. In this study, 25 apparently well-adjusted children from a pediatric primary care unit were evaluated by the CDRS. Their scores (ranging from 16 to 18) differed significantly from the normal values noted by the founders of the scale, based on the study of inpatients. On the other hand, a study of six of our clinically depressed children indicated scores of 22 to 49. With this definition of the normal score the outpatient child who scores greater than 20 is classified as in need of close follow up to determine if he is depressed.