RESUMEN
In vitro protein binding studies were conducted to examine the interaction between ceftriaxone (CEF), probenecid (PROB) and diazepam (DIAZ). The presence of PROB and DIAZ at concentrations equal to molar albumin concentration caused a decrease in CEF affinity from 3.7 x 10(4) M-1 (control) to 1.1 x 10(4) (PROB) and 2.6 x 10(4) (DIAZ) M-1, but not in binding capacity in pooled human plasma. PROB and DIAZ at five times the molar albumin concentration also caused a decrease in CEF affinity from 4.5 x 10(4) M-1 (control) to 0.45 x 10(4) (PROB) and 3.0 x 10(4) (DIAZ) M-1 in isolated human serum albumin. DIAZ and PROB displaced one another, confirming their common binding site (Site II, the benzodiazepine site) on serum albumin. By contrast, CEF was unable to displace either PROB or DIAZ from defatted albumin. In the presence of elevated free fatty acid concentrations (four times the albumin concentration), CEF decreased the binding of both drugs. CEF free fraction (fp) in isolated human serum albumin (CEF fp = 7.7%) was increased by drugs which bind to Site I: sulfisoxazole (CEF fp = 68.1%), warfarin (CEF fp = 56.0%) and furosemide (CEF fp = 55.0%). At ten times the molar concentration of albumin, CEF displaced both warfarin (warfarin fp from 0.99 to 2.20%) and phenytoin (phenytoin fp from 17.7 to 23.4%) from defatted albumin. CEF appeared to bind to Site I (the warfarin site) on human serum albumin, and was displaced by PROB and DIAZ via a mechanism which did not involve direct competition at a common binding site.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Ceftriaxona/metabolismo , Diazepam/farmacología , Probenecid/farmacología , Albúmina Sérica/metabolismo , Sitios de Unión , Proteínas Sanguíneas/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Diazepam/metabolismo , Interacciones Farmacológicas , Ácidos Grasos no Esterificados/metabolismo , Humanos , Fenitoína/metabolismo , Probenecid/metabolismo , Warfarina/metabolismoRESUMEN
Ceftriaxone binding in extravascular fluids and diluted plasma was characterized by equilibrium dialysis techniques and the data was subjected to Scatchard analysis. The extent of ceftriaxone binding in extravascular fluids (synovial, lymph, ascites, and pleural exudate) was less than plasma due primarily to lower albumin concentrations. Ceftriaxone capacity constants were highly correlated (r2 = 0.900, p less than 0.001) with measured albumin concentrations (range of 43 g/L for albumin to 4.7 g/L for one of the pleural exudate samples). The binding affinity constant (M-1 x 10(-4] was comparable for plasma (3.67), synovial fluid (4.14), and lymph (3.40), but was lower for ascites (2.37) and pleural fluid (range of 2.77 to 0.31). Plasma samples diluted with plasma water (range of 100 to 3%) exhibited a common affinity constant (mean value 4.03 x 10(4) M-1) and capacity constants which correlated directly with albumin concentration (r2 = 0.998, p less than 0.001). Analysis of these observations suggests that extravascular binding of ceftriaxone can readily be predicted if extravascular albumin concentration and corresponding disease-state plasma protein binding are known.
Asunto(s)
Ceftriaxona/metabolismo , Líquido Ascítico/metabolismo , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Exudados y Transudados/metabolismo , Humanos , Linfa/metabolismo , Unión Proteica , Líquido Sinovial/metabolismoRESUMEN
The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d. Probenecid increased the total systemic clearance (CLTS) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t1/2T (beta)) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CLFR) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone. The final value of CLFR was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CLFNR) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CLFS) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg). As a consequence of a decreased affinity constant (KA), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid. The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.
Asunto(s)
Ceftriaxona/metabolismo , Probenecid/farmacología , Adulto , Proteínas Sanguíneas/metabolismo , Ceftriaxona/sangre , Ceftriaxona/farmacocinética , Semivida , Humanos , Masculino , Probenecid/efectos adversos , Unión Proteica/efectos de los fármacosRESUMEN
The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady-state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half-life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.
Asunto(s)
Antiinflamatorios/metabolismo , Piroxicam/análogos & derivados , Compuestos de Sulfonilurea/metabolismo , Tiazinas/metabolismo , Adulto , Glucemia/metabolismo , Femenino , Humanos , Insulina/metabolismo , Cinética , Masculino , Compuestos de Sulfonilurea/sangre , Factores de TiempoRESUMEN
The disposition profile of ceftriaxone was studied in eight normal subjects and in 15 subjects with various degrees of chronic liver damage (alcoholic fatty liver [FL] and cirrhosis without [C] and with [CA] ascites) who received bolus injections of ceftriaxone, 1 gm iv. Plasma protein binding fell in all. As a result, mean free fraction in plasma rose between 140% (FL) and 320% (CA). An exceptionally large rise (1270%) occurred in one subject with CA when the condition was aggravated by renal impairment. Fourteen of 15 subjects had renal clearance of unbound drug of the same order as that in healthy adults. In chronic liver disease, mean nonrenal clearance of unbound drug fell with severity of liver damage. Kinetic parameters with reference to total drug differed in normal subjects and subjects with CA. Kinetic changes in the latter were such that elimination t 1/2 beta did not differ (9.7 and 8.4 hr). Because of the wide therapeutic range of ceftriaxone, subjects with chronic liver disease would require no dose adjustments, whereas dose reductions are envisaged for subjects with cirrhosis (C,CA) on the basis of increased unbound drug concentrations.