Disposition of SDZ ENA 713, an acetylcholinesterase inhibitor, in the rabbit.

The disposition of SDZ ENA 713, indicated for the treatment of Alzheimer's disease, was studied in non-pregnant, pregnant, and lactating New Zealand white rabbits. 3H-SDZ ENA 713 was administered as single oral or intravenous dose (1.09 mg kg-1) and as multiple oral doses (1.09 mg kg-1) daily for 7 days. Serial blood and milk samples, selected tissues and excreta samples were collected. Radioactivity was determined in all biological samples by liquid scintillation counting. Concentrations of unchanged SDZ ENA 713 and its phenolic metabolite, ZNS 114-666, were measured by GC-MS. Pharmacokinetic parameters were determined by model independent methods. The rate and onset of absorption were rapid (tmax 1.3 +/- 0.58 h) and the extent of absorption was essentially complete. Concentrations of SDZ ENA 713 were below the limit of quantification (0.98 ng mL-1) after oral administration. Following intravenous administration, SDZ ENA 713 was extensively distributed (Vss = 3.1 L kg-1) and rapidly cleared (Cl = 2.7 L h-1 kg-1). The radioactivity was primarily excreted via the kidneys (86% of dose). In pregnant rabbits receiving multiple oral doses, the fetus to placentae tissue ratio of radioactivity averaged 0.5. Passage of radioactivity from blood into milk was rapid (tmax = 2 h) and the milk:blood AUC ratio of radioactivity averaged 1.5. No unchanged SDZ ENA 713 was detected in the milk samples; however, there were measurable concentrations of the phenolic metabolite (Cmax = 82.9 ng mL-1). The milk to blood ratio of the phenolic metabolite averaged 2.3. In conclusion, SDZ ENA 713 underwent extensive presystemic metabolism following oral administration. There was moderate transfer of drug-related materials across the placenta. Projecting the rabbit data to humans, it is suggested that nursing neonates would not be exposed to unchanged SDZ ENA 713 following oral doses to nursing mothers.

Cyclosporin pharmacokinetics in paediatric transplant recipients.

Cyclosporin is an essential component of the antirejection drug protocol used in the long term management of paediatric organ transplant recipients. This article looks at the pharmacokinetics of cyclosporin in paediatric kidney, heart, liver and bone marrow transplant recipients and critically evaluates its relationship to pharmacokinetic data in adult transplant recipients. There are limited data on the pharmacokinetics of cyclosporin in paediatric transplant recipients (14 publications provide the database) as compared with the adult transplant population. Study design, analytical methodology and age ranges of the individuals differ between studies, making comparative interpretation of pharmacokinetic data difficult. However, significant trends are noteworthy and these may influence dose administration guidelines and therapeutic monitoring standards for cyclosporin in the paediatric organ transplant recipient. The bioavailability of the oral formulations of cyclosporin is highly variable as with the adult population, but there appears to be a correlation between cyclosporin bioavailability and age with both the traditional oral formulation (Sandimmun) and the new microemulsion formulation (Neoral) in young liver transplant patients. Bowel length, presystemic metabolism in the gut wall, type of transplant and time since transplant are contributing factors in the variation of bioavailability patterns in paediatric transplant patients. The volume of distribution of cyclosporin does not appear to differ between paediatric and adult transplant recipients, but systemic clearance is comparatively higher in the paediatric population. In general, paediatric patients require higher doses of cyclosporin to achieve target blood concentrations of the drug which are equivalent to the values used in the adult population. Younger patients (less than 8 years of age) may be managed more effectively with a 3 times daily administration schedule rather than the twice daily schedule which is universally used for cyclosporin in the transplant population. The comparatively higher doses and more frequent administration schedule used in paediatric transplant recipients are the consequence of age-related differences in bioavailability and the possibility of increased metabolic clearance of the drug in younger patients.

Effect of food on the bioavailability of SDZ DJN 608, an oral hypoglycemic agent, from a tablet and a liquid-filled capsule in the dog.

PURPOSE: The effect on food on the bioavailability of SDZ DJN 608, a D-phenylalanine derivative, was investigated in three mature, male beagle dogs. METHODS: Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (LC). Additionally, a 5 mg intravenous dose was given in the fasting state. Doses in the same dog were separated by 1-week washout periods. Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC. Model-independent pharmacokinetic parameters were compared between treatments by 3-way ANOVA: In vitro dissolution profiles of T and LC were generated using the USP paddle method. In addition, the transport of SDZ DJN 608 through a Caco-2 cell monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-alpha-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. RESULTS: In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing that, at both pH 1.2 and pH 6.8, the dissolution rate of LC was faster than that of T. No significant difference in the area under curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-alpha-methyldopa, suggesting passive diffusion of the former. CONCLUSIONS: Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.

Pharmacokinetics and local responses to submucosal meperidine compared with other routes of administration.

The objective of this study was to determine the time course of the plasma levels of meperidine administered by various routes. Ten healthy adults received 0.8 mg/kg of meperidine given intravenous, submucosal, intramuscular, and 1.4 mg/kg orally in a randomized sequence at a minimum of one-week intervals. Blood samples were collected at 0, 10, 20, 30, 45, 60, 90, 120, 180, 240, 360, and 720 min. The plasma was separated by centrifugation at room temperature. Plasma samples were analyzed for unchanged meperidine by a high-pressure liquid chromatographic assay. Pharmacokinetic parameters were calculated according to standard techniques. Data analysis was accomplished using a 4 x 11 analysis of variance and the Scheffe test for multiple comparisons. Pain response and tissue changes also were assessed using 4-point scales. Significant interaction effects (P < 0.00001) were found between the administration route and the time intervals. The maximum observed concentration of meperidine for the IV and SM routes occurred at the first sample point at 10 min, for the IM route at 20 min, and for the PO route at 45 min. There were no significant differences between the IV and the SM routes at any time interval measured. Post hoc comparisons of the peak values demonstrated significant differences between the IM and PO values (1.4 mg/kg) when compared with the IV and SM routes (P < 0.01). SM route caused greater tissue response and pain reaction, however, the differences were not statistically significant.

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women.

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.

Clinical pharmacokinetics in organ transplant patients.

Diseases of the liver, kidney and heart influence the pharmacokinetics of several drugs. Organ transplantation is an accepted therapeutic option for the treatment of several disease states associated with these organs. Recently, there has been an increase in both graft and patient survival after transplantation of the liver, heart, kidney and bone marrow. Such patients normally receive a wide range of drugs, and optimisation of drug therapy requires a thorough understanding of the pharmacokinetics and pharmacodynamics of these drugs in transplant patients. However, only limited studies have been carried out to characterise drug kinetics in these situations. Available information indicates that drug kinetics cannot be considered normal in transplant patients. Drug absorption generally appears to be similar to that in healthy subjects. The plasma protein binding of drugs that primarily bind to albumin increases after transplantation, but remains lower than that observed in healthy subjects. While the binding of certain basic drugs may increase after transplantation due to an increase in the concentration of alpha 1-acid glycoprotein, a lower albumin concentration may mask this effect. Oxidative and conjugative metabolism as measured by the kinetics of antipyrine (phenazone) and paracetamol (acetaminophen) is normal, while the metabolism of steroids may be impaired. Serum creatinine does not appear to be a good indicator of the functional status of the kidney in transplant patients. It is also important to realise that there will be time-dependent changes in several kinetic parameters of drugs due to improvement in the physiological function from that associated with the disease state to that of the normal state. Individualisation and close monitoring of drug therapy is necessary in transplant patients.