Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml^–1 · mol^–1; R-PPFG: 576 vs. 304 nmol · ml^–1 · mol^–1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml^–1 · mol^–1; R-PPFG: 7340 nmol · ml^–1 · mol^–1). In summary, the disposition of propafenone and of its active metabolite 5-hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.     

Effect of Anticonvulsant Drugs on Inhibitory and Excitatory Pathways

A conditioning stimulus to the periventricular gray matter inhibits the response of spinal trigeminal neurons to maxillary nerve stimulation. Sodium valproate and ethosuximide decrease the periventricular inhibition without significantly affecting the response of these neurons to the unconditioned maxillary nerve stimulus. We have now found that carbamazepine and phenytoin decrease the response to the unconditioned maxillary nerve stimulus, and only depress the periventricular inhibition secondarily. These results further support the hypothesis that the ability to depress selectively inhibitory pathways in the CNS is an important characteristic of antiabsence drugs, and that absence seizures may represent paroxysmal discharges in inhibitory pathways.     

Drug-induced gastric mucosal injury

Although there is much of anecdotal information about drug injury to the gastric mucosa, only a few agents (e.g., salicylates, nonsteroidal-nonsalicylate antiinflammatory compounds, and alcohol) have been studied in detail. The presence of acid in the gastric lumen is required for an injurious drug to cause clinically significant injury. Injury occurs as a result of the ability of certain drugs to increase the permeability of the mucosa to its own secreted acid lying within the lumen. As the tissue becomes overwhelmed by the diffusing acid, cell death occurs. Drugs that increase the diffusion of acid also interfere with cellular metabolism, an effect that is independent of the ability of the drug to increase diffusion of acid from the lumen into the tissue. However, when metabolic processes of the mucosa are depressed, the ability of the tissue to buffer diffusing acid is impaired. Thus, the quantity of acid diffusing into the tissue is not as important as the buffering capacity of the mucosa. Most instances of drug-induced injury are not clinically apparent, yet significant hemorrhage occurs in some patients. Even though the initial episode of hemorrhage may be severe, aggressive nonoperative treatment usually is sufficient, provided the mucosa is no longer exposed to the injurious agent. Only a few patients require operation, the extent of which is still controversial.

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Résumé S'il existe de nombreuses informations anecdotiques sur les lésions de la muqueuse gastrique produites par des médicaments, quelques drogues seulement ont été étudiées en détail (salicylés, alcool, anti-inflammatoires non stéroidiens et non salicylés, par exemple). La présence d'acide dans la lumière gastrique est indispensable pour que le médicament cause une lésion ayant une traduction clinique. Certains médicaments accroissent la perméabilité de la muqueuse à l'acide secrété et déversé dans la lumière. Cette rétrodiffusion d'acide provoque la mort cellulaire. Les mêmes médicaments perturbent également le métabolisme cellulaire. Cette action est indépendante de la capacité de la drogue à produire la rétrodiffusion d'acide. Mais, la dépression du métabolisme cellulaire entraîne également une réduction de la capacité des cellules à neutraliser l'acide. La quantité d'acide qui diffuse de la lumière vers les cellules est donc moins importante que la capacité de neutralisation de la muqueuse. Dans la majorité des cas, les lésions produites par les médicaments n'ont pas de traduction clinique. Dans certains cas cependant, des hémorragies apparaissent. Un traitement médical actif, sans intervention chirurgicale, est en général suffisant, même si l'hémorragie initiale est grave, à condition que la muqueuse gastrique ne soit plus exposée à l'agent délétère. Les indications opératoires sont rares. Le type d'opération à réaliser reste très discuté.

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Supported by AM-25227 from the National Institutes of Health, United States Public Health Service.