Alterations in Renal Uptake Kinetics of the Xanthine Derivative Enprofylline in Endotoxaemic Mice

The pharmacokinetics and renal uptake of enprofylline, which is primarily excreted into the urine by an active tubular secretion mechanism, were investigated in endotoxaemic mice by lipopolysaccharide isolated from Klebsiella pneumoniae. Lipopolysaccharide (1 mg kg^?1) was infused 2 h before starting the examination, thereby inducing a decrease in the systemic clearance and an increase in the steady-state volume of distribution of enprofylline while inducing no changes in the urinary recovery (> 90%). The protein binding of enprofylline significantly decreased in the presence of lipopolysaccharide. Both the systemic clearance for unbound enprofylline and glomerular filtration rate decreased in the treated mice. A nonlinear relationship was found in both groups between the steady-state unbound plasma concentration and renal uptake of enprofylline after constant infusion for 1 h. The renal uptake rate of enprofylline decreased in the treated mice. Lipopolysaccaharide caused increases in the apparent maximum capacity for renal uptake (V_max) from 17.3 to 32.2 μg h^?1 g^?1 of kidney and in the Michaelis–-Menten constant (K_m) from 2.7 to 21.7 μg mL^?1 and decrease in the nonsaturable uptake rate constant (K_d) from 0.87 to 0.43 mL h^?1 g^?1 of kidney. These results indicate that lipopolysaccharide decreases the renal tubular secretion of enprofylline by inducing a decrease in the renal uptake ability.     

Effects of ozolinone,a diuretic active metabolite of etozoline,on renal function

Summary The renal action of 3-methyl-4-oxo-5-piperidino-thiazolidine-2-ylidine (ozolinone), a metabolite of the diuretic etozoline (Elkapin), was studied in anaesthetized dogs after i.v. injection and compared with the renal effects of furosemide. The diuretic action of ozolinone was rapid in onset and of short duration. Thesmallest effective i.v. dose was 1 mg\kg^–1. Maximal diuretic capacity was reached at 50 mg\kg^–1 i.v. Fractional tubular sodium reabsorption was depressed to 67% at maximal effective doses.Ozolinone had similar renal actions to those of furosemide. Like furosemide, ozolinone increased renal blood flow, slightly decreased glomerular filtration rate, depressed tubular chloride reabsorption more than sodium reabsorption, increased potassium excretion, lowered the pH of urine, decreased urinary osmolarity towards isotonicity and depressed tubular PAH secretion. As regards the effective doses and the maximal changes of tubular sodium excretion, ozolinone was somewhat less potent than furosemide.     

Influence of Age on the Disposition and Renal Handling of Enprofylline in Rats

Abstract— The effects of ageing on the pharmacokinetics, renal handling and protein binding of enprofylline were investigated in 6-, 13- and 18-month-old male Fischer 344 rats. Concentrations of enprofylline in plasma and urine were determined by HPLC, and pharmacokinetic parameters were estimated by model-independent methods. No significant differences in the volume of distribution, systemic clearance of enprofylline or urinary recovery of unchanged enprofylline (> 85%) were observed among any of the groups of rats. The dissociation constant and free fatty acid concentration in plasma increased with age. Age-dependent decreases in the systemic clearance for unbound drug were observed, and the volume of distribution for unbound drug tended to decrease with age. The ratio of systemic clearance for unbound drug to the glomerular filtration rate (GFR) decreased with ageing. Ageing was associated with decreases in the apparent maximum capacity of transport (V_max) (223·33,160·24 and 142·98 μg min^?1 kg^?1 for 6-, 13- and 18-month-old rats, respectively) and in the tubular secretory intrinsic clearance (V_max/K_m) of enprofylline (75·45, 51·03 and 44·13 mL min^?1 kg^?1, respectively), while a slight change in the Michaelis-Menten constant (K_m) was observed. These results indicate that the mechanism responsible for age-related changes in the disposition and renal handling of enprofylline may be responsible for a decrease in the ability of the tubular anion transport system.     

Disposition Characteristics of Protein Drugs in the Perfused Rat Kidney

The renal disposition characteristics of ¹¹¹In-labeled neocarzinostatin (NCS), soybean trypsin inhibitor (STI), and superoxide dismutase (SOD) were studied in the perfused rat kidney. In a single-pass indicator dilution experiment, venous and urinary recovery profiles and tissue accumulation of proteins were determined under filtering or nonfiltering conditions. In the nonfiltering kidney perfusion experiment, no significant tissue accumulation was observed, suggesting minimal uptake from the glomerular and peritubular capillary sides. Therefore, tissue recovery corresponded to that with tubular reabsorption after glomerular filtration. The total amount of NCS or STI being filtrated through glomeruli, the sum of tissue and urinary recoveries, was similar to that of inulin, but that of SOD was about half. Similarly, the steady-state distribution volumes (V _d) of NCS and STI obtained by moment analysis of their venous outflow curves were similar to that of inulin, while the V _d value of SOD was significantly lower. These results suggest the restricted passage of SOD through the glomerular and postglomerular capillary wall. The tubular reabsorption ratio of proteins against the total filtrated amount decreased with an increase in the administered dose, suggesting nonlinearity of reabsorption. SOD had the largest reabsorption ratio. Thus, this experimental system is useful for quantitative analysis of renal disposition of proteins.     

The Effect of Lipopolysaccharide on the Disposition of Xanthines in Rats

Abstract— The effect of lipopolysaccharide (LPS) isolated from Klebsiella pneumoniae O3 on the pharmacokinetic behaviour and metabolism of the xanthines, theophylline and 1-methyl-3-propylxanthine (MPX), which are mainly metabolized by the liver, was investigated in rats. LPS was infused at 0·25 mg kg^?1 over a period of 20–30 min, 2 h before the administration of theophylline (10 mg kg^?1) or MPX (2·5 mg kg^?1). Concentrations of both xanthines in plasma and concentrations of the parent drug and metabolites in urine were measured by HPLC. Model-independent methods were applied to estimate the pharmacokinetic parameters for both xanthines. No significant changes in the pharmacokinetic parameters or metabolism of theophylline were observed in rats pretreated with LPS. However, the total body clearance and volume of distribution of MPX were significantly increased by pretreatments with LPS. Significant decreases in the binding capacity and number of binding sites on the albumin molecule were observed in the presence of LPS. Changes occurring in the protein binding behaviour as a result of the introduction of LPS is a primary factor which not only increases the volume of distribution but also increases total body clearance. These results indicate that LPS has no effect on the pharmacokinetics and metabolic pathway of theophylline although it changes the disposition of MPX due to decreases in the extent of the protein binding of MPX which is highly bound to protein.     

Nonlinear kinetics of the thiamine cation in humans: Saturation of nonrenal clearance and tubular reabsorption

The pharmacokinetics of thiamine in plasma and urine was investigated in 13 healthy and 3 renal-insufficient volunteers. Doses ranging from 5 to 200mg thiamine hydrochloride were administered either as an iv bolus or a 50-min infusion. A sum of 3 exponentials was used as the unit impulse response function to characterize plasma kinetics. Drug input was mathematically described as a rectangular pulse of length 2 or 50 min. Total clearance, defined as the reciprocal of the area under the unit impulse response function, was found to depend on dose and creatinine clearance, as shown by a multiple nonlinear regression analysis. The nonrenal component of the total clearance was demonstrated to be dose-dependent, whereas its meanrenal component was only dependent on creatinine clearance. At high plasma concentrations renal clearance approached renal plasma flow, and remained constant during the decline to near physiological plasma levels. With further decline under a characteristic threshold concentration, renal clearance decreased far below the glomerular filtration rate, indicating tubular reabsorption. Binding to plasma proteins was excluded by ultrafiltration experiments. The process of renal excretion can be described by a combination of glomerular filtration, flow-dependent tubular secretion, and saturable tubular reabsorption. The concentration dependency of renal clearance was reflected in its mean value, which was only 76% of its maximum value measured in the higher concentration range. In the dose range studied, most of the given dose had already been linearly excreted before tubular reabsorption became evident, and consequently the measured mean renal clearances did not differ enough from one another to exhibit the expected dose dependency. With increasing dose a shift of the cleared dose fraction from the nonrenal to the renal side was observed. Saturated nonrenal clearance alone could explain this effect.     

The Effects of N-Benzoyl-β-alanine,a New Nephroprotective Drug,on the Distribution and Renal Excretion of Enprofylline in Rats

Abstract— The effects of the new nephroprotective drug N-benzoyl-β-alanine (BA) on the disposition and renal excretion of the bronchodilator enprofylline, which is actively secreted in urine, were investigated in rats. Enprofylline was administered intravenously at a dosage of 2·5 mg kg^?1 under three different steady-state plasma BA concentrations (100,200 and 400 μg mL^?1) which were achieved by constant infusion rates. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. The presence of BA (400 μg mL^?1) increased the systemic clearance by 25% and the volume of distribution at steady-state by 90%. A significant increase in the dissociation constant, which is the protein binding parameter of enprofylline was observed in the presence of BA (400 μg mL^?1), indicating that BA competitively inhibits the protein binding of enprofylline. However, BA significantly decreased the systemic clearance and volume of distribution for unbound enprofylline. These results suggest that BA, the organic anion transport inhibitor, inhibits renal excretion of enprofylline with a high affinity for renal tubular secretion, although the unbound concentration of enprofylline increases with administration of BA. We conclude that BA decreases the renal tubular secretion of enprofylline probably by reducing the affinity of the tubular transport system, and that these changes have marked effects on the pharmacokinetic behaviour of enprofylline.     

Digoxin-specific Fab fragments impair renal function in the rat

Abstract— The effect on renal function, and the plasma and urinary disposition, of digoxin-specific antibody fragments (DSFab), were studied using the rat as an experimental model. After 24 h, DSFab (2 mg kg^?11, i.v.) caused decreases in urine volume and creatinine clearance of 34 and 33%, respectively, when measured in the same rats. However, only the creatinine clearance was significantly changed when compared with a separate saline-treated control group. Plasma and urinary creatinine concentrations were unaffected by DSFab treatment. Since creatinine clearance approximates to glomerular filtration rate (GFR), it appears that a dose of DSFab equivalent to about one-fifth of the usual clinical dose, causes a reduction in GFR of about one-third. In patients undergoing digitalis therapy, a degree of renal impairment is common and it is possible that this may be exacerbated by treatment with DSFab. DSFab had an elimination half-life of 178 min, an apparent volume of distribution (Vd) of 106 mL kg^?1 and a plasma clearance of 0·42 mL kg^?1 min^?1. If it is assumed that the plasma volume of a rat is approximately 35 mL kg^?1, the measured Vd suggests appreciable penetration of DSFab into the extracellular fluid at this dose. Seventy-two hours after injection, only 7·6% of the administered dose of DSFab was found in the urine.     

Pharmacokinetics of SUN 1165, a new antiarrhythmic agent,in renal dysfunction

Summary The pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg.The apparent volume of distribution at steady state was 1.48 1 · kg^–1, the absorption rate constant was 2.2 h^–1, and plasma protein binding was 26.8% in subjects with normal renal function.These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration.The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml · min^–1 · 1.48 m^–2).Dosage adjustment of SUN 1165 is necessary in renal failure.     

Effects of dopamine on whole kidney function and proximal transtubular volume fluxes in the rat

Summary The renal effects of dopamine were studied using clearance and micropuncture techniques in rats. Intravenous infusion of dopamine (4.7 · 10^–6 mol · kg^–1 · h^–1) increased glomerular filtration rate and renal blood flow. Renal blood flow was measured by an electromagnetic flowmeter. The increase in filtered fluid and sodium was nearly completely matched by increased tubular reabsorption. Thus, only a small rise in urine flow and in urinary sodium excretion was observed.The micropuncture experiments using the split oil droplet method of Gertz demonstrated a stimulation of the transepithelial fluid transfer after injection of dopamine (10^–4M) into the proximal tubular lumen. This effect was abolished by simultaneous injection of propranolol (10^–3 M) which, by its own, did not affect transtubular volume fluxes. It is concluded that dopamine, by stimulation of -adrenoceptors, may increase reabsorptive capacity of the proximal tubular epithelium independent of changes in renal hemodynamics.Supported by Deutsche Forschungsgemeinschaft     

Renal and hormonal effects and tolerance of an ANP analogue in healthy man

Summary The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 g·kg^–1 bwt were given as an intravenous bolus injection to different groups.P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min.Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E₂ were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner.P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30–60 min after injection of P-ANP.It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man.     

Der renale Sauerstoffverbrauch nach Strophanthin und 6-Aminonicotinamid

Summary The effects of i.v. injections of 100 mg/kg of 6-Aminonicotinamide (6-AN) and of infusions of 0.5/kg · min Ouabain into one renal artery on urine volume, renal blood flow, glomerular filtration rate, tubular sodium reabsorption (TNa), renal oxygen consumption (VO₂) and on the ratio TNa/VO₂ has been investigated in anesthetized dogs.6-AN had no effects on urine volume and on tubular Na-reabsorption in dogs although the latter was decreased in rats (Herkenet al., 1964). The renal oxygen consumption, however, was increased by some 30%. Hence the ratio TNa/VO₂ was lowered because of the enhanced denominator and constant numerator.The intrarenal infusions of Ouabain increased the urine volume and partially blocked the tubular Na-reabsorption. The renal oxygen consumption decreased proportionally. Thus the ratio TNa/VO₂ was not different from the control values. It was concluded therefore that Ouabain diminishes the net reabsorption of sodium by direct blocking of the active, energy consuming sodium transport in contrast to typical diuretics like Furosemide (Fülgraffet al., 1969) or ethacrynic acid (Wolfet al., 1969), which according to our former hypothesis decreased the net transfer of Na rather by changing the membrane permeability.

     

Attenuation of adenylate cyclase-induced increases in renal sodium excretion by the dopamine D-2 receptor agonist SK&F 89124

1 Although the existence of D-2 receptor binding sites in kidney has been identified, their functional significance in terms of influencing renal sodium excretion is not clear. In the present study we have examined the renal effects of a selective D-2 receptor agonist, SK&F 89124, in anaesthetized rats. 2 Intravenous infusion of SK&F 89124 (0.3, 1 and 3 μg kg^?1 min^?1 respectively) produced dose-dependent decreases in mean arterial blood pressure, heart rate and renal blood flow without causing any significant changes in urine output, urinary sodium excretion, renal vascular resistance or glomerular filtration rate. The changes in blood pressure, heart rate and renal blood flow caused by SK&F 89124 were abolished by a selective D-2 receptor antagonist, domperidone (50 μg kg^?1 i.v. bolus; 10 μg kg^?1 min^?1). 3 Treatment with 3-isobutyl-l-methylxanthine (IBMX, 1 mg kg^?1 bolus i.v.) or forskolin (200 μg kg^?1 bolus i.v.) produced increases in heart rate, urine output and urinary sodium excretion, but there was no change in mean blood pressure. The natriuretic and diuretic response, but not tachycardiac response to IBMX or forskolin, was attenuated by SK&F 89124 (0.3 μg kg^?1 min^?1). 4 These results suggest that the selective D-2 receptor agonist, SK&F 89124, produced a significant decrease in blood pressure and heart rate via prejunctional D-2 receptor-mediated inhibition of noradrenaline release from postganglionic sympathetic nerve terminals. Although activation of renal tubular D-2 receptors had no significant effect on renal excretory function under basal conditions, it is likely that these receptors may exert an opposing effect on cAMP-mediated increases in renal sodium and water excretion.     

Pharmacokinetics,toxicokinetics, distribution,metabolism and excretion of linezolid in mouse,rat and dog

1. Linezolid (ZYVOX?), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg^?1 day^?1) and dog (10-80mg kg^?1 day^?1) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V_ss) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.     

Effects of acute exposures to gentamicin on renal handling of proteins

The polycationic aminoglycoside gentamicin has been reported to compete with other aminoglycosides and cationic compounds for uptake into renal tubular cells at brush border membranes and during subsequent endocytosis. Gentamicin has also been reported to decrease the activity of lysosomal proteolytic enzymes in the rat kidney.In vivo and in vitro experiments were carried out to determine the effect of acute exposure to gentamicine on renal handling of the cationic low molecular weight protein, lysozyme. Thirty or 60 mg/kg of gentamicin was given to male Wistar rats (250–300 g) intravenously or isolated rat kidneys were perfused with gentamicin concentrations of 0.25, 0.50, 1.0 and 2.5 mg/ml. Subsequently, clearances of lysozyme (C_LY) and inulin (GFR, glomerular filtration rate) were measured in the intact rat and in the isolated perfused rat kidney. The glomerular sieving coefficient of lysozyme was determined in control and gentamicin perfused kidneys after complete inhibition of tubular lysozyme reabsorption by sodium iodoacetate. Renal degradation of ¹²⁵I-labelled lysozyme was quantified in control and gentamicin perfused kidneys by measuring the release [¹²⁵I] monoiodotyrosine to the perfusate.The glomerular sieving coefficient of lysozyme increased in kidneys perfused with gentamicin from a control value of 0.8-1.0. A dose-dependent increase of the ratio C_LY/GFR in intact rats treated with gentamicin and dose-dependent decrease of percentage reabsorption of lysozyme in the isolated perfused kidneys demonstrate inhibition of renal reabsorption of lysozyme by gentamicin. Perfusion of kidneys with 0.25 mg/ml gentamicin reduced renal degradation of lysozyme to about 50% after 2h perfusion; at gentamicin concentrations of 0.5 mg/ml and higher almost all degradation of lysozyme was inhibited.Thus acute exposure to gentamicin causes impairment of filtration, tubular reabsorption and catabolism of the protein lysozyme, effects which are due to pharmacological interactions between the molecules of the 2 cations gentamicin and lysozyme.     

Apparent dose-dependent oral absorption of cyclosporin a in rats

The oral absorption of cyclosporin A (CyA) was studied in rats after 6, 12, 18, and 23 mg kg^?1 doses were given in an olive oil solution to determine if CyA absorption from the gastrointestinal tract was dose-dependent. Using serial blood samples obtained at various times after the respective doses, analysis of the resultant blood CyA concentration–time curves suggested that the rate of CyA absorption for all four doses was an apparent zero-order process. Moreover, the rate of CyA absorption appeared to be dose-dependent, increasing as the dose of CyA increased. Similarly, the extent of CyA absorption (F) also exhibited dose-dependent characteristics in this study. F is increased from 0·13 after the 6 mg kg^?1 dose to 0·22 with the 18 and 23 mg kg^?1 doses (p < 0·05). In the present investigation, the observed values for the duration of drug absorption (T), terminal first-order rate constant (β) and corresponding elimination half-life (T_1/2β) of approximately 4–5 h, 0·030 h^?1 and 21–28 h, respectively, were similar for all CyA doses. Moreover, no difference in β was observed after oral or intravenous drug administration. Absorption lag times of 1–2 h were found. The results suggested that the apparent dose-dependent absorption of CyA observed in the present study was possibly related to the effects of olive oil on gastric emptying and that CyA might be unstable in the gastric fluids and/or metabolized by the gastric mucosa.     

The estimation of the plasma free fraction of cyclosporine in rabbits and heart transplant patients: The application of a physiological model of renal clearance

We estimated the free fraction (f_u) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (C_u) and plasma (C_p), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5–30 mg kg^?1) in ten NZW rabbits and oral administration of CyA (4.8–12.1 mg kg^?1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of C_u to C_p and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between C_u and C_p at any urine flow rate was reached and, therefore, the C_u to C_p ratio will not be equal to f_u.     

Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine

In this study the pharmacokinetics and pharmacodynamics of morphine-3-glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 μmol kg^?1) and as a constant rate infusion (2.9 μmol h^?1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 ± 0.6 ml min ^?1* kg, the volume of distribution at steady state (V_ss) 1.68 ± 0.89 1 kg^?1, the half-life of the first phase 13.2 ± 1.8 min and the halflife of the second phase 11.6 ± 7.7 h. After the constant rate infusion, Cl was 10.5 ± 1.7 ml min^?1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 μmol kg^?1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.     

Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice

1.?Cefadroxil is a broad-spectrum β-lactam antibiotic that is widely used in the treatment of various infectious diseases. Currently, poor understanding of the drug’s pharmacokinetic profiles and disposition mechanism(s) prevents determining optimal dosage regimens and achieving ideal antibacterial responses in patients. In the present retrospective study, we developed a population pharmacokinetic model of cefadroxil in wild-type and Pept2 knockout mice using the nonlinear mixed effect modeling (NONMEM) approach.

2.?Cefadroxil pharmacokinetics were best described by a two-compartment model, with both saturable and nonsaturable elimination processes to/from the central compartment. Through this modeling approach, pharmacokinetic parameters in wild-type and Pept2 knockout mice were well estimated, respectively, as follows: volume of central compartment V₁ (3.43 versus 4.23?mL), volume of peripheral compartment V₂ (5.98 versus 8.61?mL), intercompartment clearance Q (0.599 versus 0.586?mL/min) and linear elimination rate constant K₁₀ (0.111 versus 0.070?min^?1). Moreover, the secretion kinetics (i.e. V_m1?=?17.6?nmoL/min and K_m1?=?37.1?µM) and reabsorption kinetics (i.e. V_m2?=?15.0?nmoL/min and K_m2?=?27.1?µM) of cefadroxil were quantified in kidney, for the first time, under in vivo conditions.

3.?Our model provides a unique tool to quantitatively predict the dose-dependent nonlinear disposition of cefadroxil, as well as the potential for transporter-mediated drug interactions.     

The pharmacokinetics and absolute bioavailability of selegiline in the dog

Selegiline is beneficial to Parkinsonian patients as an adjunct to levodopa therapy. Currently no pharmacokinetic data are available for selegiline in the literature, mainly due to lack of analytical methods that can measure concentrations below 10 ng mL^?1 in plasma. A sensitive fluorimetric assay based on inhibition of rat brain monoamine oxidase-B (MAO-B) in vitro has been developed to measure selegiline in plasma as low as 0.25 ng mL^?1. The pharmacokinetics of selegiline were investigated following intravenous and oral administration to four female mongrel dogs. Each dog received 1 mg kg^?1 selegiline in solution via gavage or by an intravenous route separated by one week. The mean terminal half-life, volume of distribution of the central compartment, and systemic clearance of selegiline were 60.24 ± 9.56 min, 6.56 ± 0.56 L kg^?1, and 159.91 ± 19.28 mL min^?1 kg^?1, respectively. After oral administration selegiline appeared to be absorbed rapidly with a t_max and C_max of 25 ± 5.8 min and 5.2 ± 1.36 ng mL^?1, respectively. The absolute bioavailability of selegiline in the dog was 8.51 ± 3.31%.