Effects of ibuprofen on the disposition kinetics of phenytoin in pregnant rats

The effects of ibuprofen on maternal phenytoin pharmacokinetics and fetal phenytoin acquisition were investigated in 19-day gestation Sprague-Dawley rats. A 5 mg kg-1 bolus injection of 14C-phenytoin was given with and without (control) pretreatment with 12.5 mg kg-1 of ibuprofen. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three-compartment maternal-fetal model. Ibuprofen pretreatment increased the maternal plasma clearance of phenytoin about three-fold and the overall apparent volume of distribution almost four-fold. No changes in the volume of the maternal central compartment or terminal first-order disposition rate constant were observed. Additionally, the maternal-to-fetal clearance of phenytoin was not altered in the ibuprofen-treated rats. No differences in the apparent fetal volume of distribution or areas under the fetal phenytoin concentration-time curves were observed between the control and ibuprofen-treated rats. The results of this study were consistent with ibuprofen-induced alterations in organ and tissue blood perfusion and demonstrated that, while the maternal disposition kinetics of phenytoin were altered by sodium ibuprofen coadministration, the maternal changes did not affect the extent of fetal exposure to phenytoin.     

Phenytoin disposition in the pregnant rat. Dose-dependent studies and salicylate effects

Studies were conducted in 19-day gestation Sprague-Dawley rats to investigate the dose dependency and effects of salicylate coadministration on phenytoin disposition during pregnancy. After iv loading doses of both drugs, concurrent iv infusions of 75.6, 151.2, or 302.4 micrograms/min/kg of 14C-phenytoin and 65, 130, or 195 micrograms/min/kg of salicylate were administered for 180 min. Maternal plasma, fetal plasma, and whole fetus samples were obtained during the infusions, and maternal tissue (heart, skeletal muscle, fat, liver, and brain) and cerebrospinal fluid specimens were collected at the termination of drug administration. All samples were assayed for phenytoin and p-hydroxydiphenylhydantoin by liquid scintillation counting following separation by TLC. Systemic and intrinsic phenytoin clearance, which averaged 12 and 41.5 ml/min/kg, respectively, for the three phenytoin infusions, were both dose independent, and were unaltered by the three salicylate treatments. Similarly, the maternal tissue-to-plasma concentration ratios for phenytoin and p-hydroxydiphenylhydantoin were dose and/or concentration independent following the three phenytoin infusions, and were also not affected by salicylate coadministration. Additionally, the fetal distribution ratios for whole fetus-to-maternal plasma and whole fetus-to-fetal plasma were also invariant for the three phenytoin infusions and salicylate treatments. The results showed that the maternal and fetal disposition of phenytoin was dose and concentration independent and unaltered by salicylate coadministration with the dosages studied.     

Effect of folic acid on the pharmacokinetics of acutely administered phenytoin in pregnant and nonpregnant rats

The concentrations of both total and free phenytoin in the plasma of epileptic women tend to decrease during pregnancy, suggestive of a pregnancy-associated increase in the metabolic clearance of the drug. On the other hand, the metabolic clearance of free (unbound) phenytoin decreases during pregnancy in rats. One possible reason for this species difference is the routine dietary supplementation of folic acid in human pregnancy and the apparent ability of folic acid to lower phenytoin plasma concentrations even in nonpregnant humans. The purpose of this investigation was to determine the effect of treatment with folic acid on the pharmacokinetics of phenytoin in pregnant and female nonpregnant rats. In one experiment, the treated animals received folic acid in the drinking water, approximately 100-150 micrograms/kg/d, for 19 d. There was no apparent difference between the treated and untreated rats in the pharmacokinetics of a 10-mg/kg iv dose of phenytoin (which was administered to the pregnant rats on the 20th day of gestation), regardless of pregnancy status, In another experiment, pregnant and female nonpregnant rats received either folic acid, 400 micrograms/kg/d, or an equal volume of the solvent only, by gastric intubation for 19 d. The next day (which was the 20th day of gestation for the pregnant rats), the animals received an intravenous injection of phenytoin, 30 mg/kg. Again, pretreatment with folic acid had no apparent effect on the pharmacokinetics of phenytoin in both pregnant and nonpregnant rats. However, the results of this investigation confirm previous observations of dose-dependent phenytoin pharmacokinetics in rats and of decreased clearance of free phenytoin in late pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics, metabolism and disposition of salicylate in protein-deficient rats

The influence of dietary protein deficiency on the pharmacokinetics, metabolism, and disposition of sodium salicylate was investigated in Sprague-Dawley male rats. Animals were fed for 3 weeks a 21% (control) or a 5% (deficient) protein diet ad lib.; an additional group of rats (pair-fed controls) was fed for 3 weeks the control 21% protein diet in a restricted quantity (10 g/day/rat), which was approximately equal to the quantity (9.8 g/day) consumed by rats receiving the 5% protein diet ad lib. Sodium salicylate (in salicyclic acid equivalents) and its metabolites were assayed by HPLC. In both control and protein-deficient rats, sodium salicylate kinetics were dose-dependent and the decline in its plasma concentration proceeded according to a first-order process; no differences in the two groups of animals were found with respect to the following features of the biological fate of salicylate: plasma half-life and clearance at a 2-mg/kg (iv) dose level, volume of distribution at all dose levels (2, 10, and 100 mg/kg, iv), relative bioavailability by oral route, tissue distribution, and the rate of urinary excretion of salicyl glucuronides at 10-mg/kg dose level. However, at high dose levels (10 and 100 mg/kg, iv), the plasma half-life of salicylate was shorter and its clearance greater in protein-deficient than in control rats. The following additional changes were caused by dietary protein deficiency: a decrease in salicylate binding to serum protein, an increase in the metabolic transformation of salicylic acid to its glycine conjugate, salicyluric acid, by kidney mitochondrial preparations, an increase in the urinary excretion of salicyluric acid and salicylic acid, and a decrease in the elimination half-life of salicylic acid; the excretion of salicyluric acid proceeded according to a first-order process in protein-deficient rats but according to an apparent zero-order process in the controls. The changes in the plasma half-life and clearance of salicylate in pair-fed controls were not significant; it appears that a deficiency of both proteins and calories (protein-deficient rats) exerts greater influence on the biological fate of salicylate than does a deficiency mainly of calories (pair-fed controls). It is suggested that the decrease in the plasma half-life of salicylate in protein-deficient rats is the result of an increase in its clearance, which in turn is caused by a decrease in protein-salicylate binding and an increase in the metabolism of salicylic acid to salicyluric acid. These results point to the desirability of a systematic study of the biological fate of salicylate during clinical malnutrition, which is common in developing countries.     

Effects of sodium salicylate on elimination kinetics of indomethacin and bile production in dogs

We investigated the effects of sodium salicylate on the elimination kinetics of indomethacin in bile duct-cannulated beagles. Indomethacin and metabolites were quantified by HPLC in plasma, bile, and urine. Indomethacin was administered as iv bolus injection and iv infusion to yield a steady-state plasma concentration of approximately 1 microgram/ml. Following sodium salicylate, given either iv (25 mg/kg) or via duodenal fistula (50 mg/kg), the indomethacin plasma level dropped instantaneously by 60-70%. Concomitantly, total systemic clearance from the plasma and biliary clearance were increased significantly. In addition, a reduced plasma protein binding of indomethacin and a significant increase in the volume of distribution were observed. The amount of indomethacin, excreted as free and conjugated drug in bile, was significantly increased temporarily by sodium salicylate. The total amount eliminated in bile (approximately 70% of the dose), however, was not changed by sodium salicylate co-administration. The bile flow was significantly enhanced for at least 4 hr. Both phase 1 metabolism and renal excretion of indomethacin remained practically unaffected by sodium salicylate treatment.     

Drug interaction. Effects of salicylate on pharmacokinetics of valproic acid in rats

The effects of salicylic acid on the pharmacokinetics of valproic acid were investigated in bile-exteriorized rats. A 50 mg/kg bolus dose of sodium valproate was injected iv to Long Evans rats with and without (control) prior treatment by constant infusion of salicylate to keep it at steady state plasma level (about 250 micrograms/ml). The plasma elimination of valproic acid followed a monoexponential decline in both salicylate-treated and control rats. A significant increase (p less than 0.01) in the disposition rate constant (kel), the volume of distribution (Vd), and the total clearance (Cltot) as well as a significant decrease (p less than 0.01) in the AUC and the elimination half-life (t1/2) were observed in the salicylate-treated rats. In spite of the significantly lowered total plasma level and increased unbound fraction of valproic acid in the salicylate-treated rats, there were no significant differences in unbound valproic plasma levels and unbound valproate pharmacokinetic parameters. The biliary excretion of unchanged and conjugated valproate was not significantly different between the two groups. The in vitro plasma-unbound fractions (fu) of valproic acid were significantly increased (p less than 0.01) in the presence of salicylic acid. The apparent dissociation constant of plasma protein binding for valproic acid was increased from 0.287 to 1.204 mM in the presence of salicylic acid. These findings indicate that the pharmacokinetic changes of valproic acid in the presence of salicylic acid were consistent with the elevation in the plasma-unbound fraction of valproic acid due to displacement from plasma protein-binding sites by salicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cysteine on the pharmacokinetics of intravenous phenytoin in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigated after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities were significantly smaller (164, 103 and 95.3 pmol/min per mg protein for the control rats, and rats with PCM and PCMC, respectively) than that in control rats. In rats with PCMC, the intrinsic clearance of phenytoin, CL(int) was significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pHPPH could be reduced in rats with PCM and PCMC. This was supported by significantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) in rats with PCM and PCMC than that in control rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 microg/min), apparent volume of distribution in central compartment (44.4, 65.4 and 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-time curve from time zero to time infinity (609, 714 and 1210 microg min/ml), renal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excretion (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were not returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activity in rats with PCMC was not returned to control level.     

Metoclopramide pharmacokinetics in pregnant and nonpregnant sheep

The pharmacokinetics of metoclopramide was studied in chronically instrumented pregnant and nonpregnant sheep. Metoclopramide was administered to the ewe by intravenous bolus injections (on a crossover basis) of 10, 20, and 40 mg, with an additional 80-mg dose to the nonpregnant animals. Transfer of the drug to the fetus was rapid with significant concentrations in fetal plasma 1 min after maternal dosing. The ratio of fetal-to-maternal area under the plasma concentration-time curves averaged 0.74, indicating significant fetal exposure to the drug. Maternal metoclopramide administration resulted in minimal fetal effects, with no change in arterial pressure, heart rate, or arterial pH or PCO2, and only a small (approximately 1.8 mmHg) transient decline in PO2. Plasma concentrations in maternal and fetal plasma in most animals were best described by a biexponential equation with rapid distribution and elimination phases. The terminal elimination half-lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively, with fetal half-life being significantly longer. The number of fetuses present had no consistent effects on either maternal or fetal pharmacokinetic parameters. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg, respectively, in the pregnant ewe, and 4.5 L/h/kg and 6.9 L/kg, respectively, in the nonpregnant animals. The terminal elimination half-life in the nonpregnant ewes averaged 67.5 min. Pharmacokinetic parameters were compared in the pregnant and nonpregnant ewes at the 10-, 20-, and 40-mg doses, and no significant differences were observed in the distribution or elimination rate constants, elimination half-life, or volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of pregnancy on tissue distribution of salicylate in rats

The effect of pregnancy on tissue distribution of salicylate was studied by comparing both pharmacokinetic and protein-binding parameters between 20-day-pregnant rats and nonpregnant (control) rats. In the pregnant rats, the volume of distribution increased significantly (p less than 0.05) from 164 ml/kg of the control to 225 ml/kg, and the total body clearance also increased significantly (p less than 0.05) from 12.1 ml/hr/kg of the control to 19.8 ml/hr/kg. But these changes did not affect the plasma disappearance half-life of salicylate in the pregnant rats. The serum unbound fraction (fs) of the pregnant rats at 8 hr after iv administration of salicylate increased remarkably from 0.14 of the control to 0.67. The fs in the fetal serum (0.41) was lower than that in the maternal serum in spite of the lower albumin concentration in the fetal serum. A nonlinear serum protein binding was observed both in the control and in the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-serum concentration ratios (Kp) of all tissues studied were larger than those in the control rats, and the values of Kp in the fetal were larger than those in the maternal. To elucidate these difference in Kp values between the pregnant and control rats, a mathematical model was proposed, where salicylate was distributed in the interstitial fluid, bound to the interstitial albumin, and translocated into the intracellular fluid according to the pH partition theory. The Kp values of most tissues in the control and pregnant rats were predicted successfully by using this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of age, sex, pregnancy and protein-calorie malnutrition on the pharmacokinetics of salicylate in rats

The influence of age, sex, pregnancy and protein-calorie malnutrition (PCM) on the plasma t1/2, plasma clearance (Clp) and apparent volume of distribution (Vd) of sodium salicylate (62 mumol kg-1) was determined in Sprague-Dawley rats. Female and male rats of five different age groups (ages in weeks: pups 1, weanling 3, young 8-9, adult including pregnant 14-15, old 56-60) including three age groups with PCM (8-9, 14-15 and 56-60 weeks old) were used. Plasma and urinary salicylates were assayed by h.p.l.c. Plasma t1/2 was longer and Clp smaller in pups than in weanling and young rats and comparable to values for old rats; Vd of salicylate in pups was larger than in any other group of rats. Plasma t1/2 was longer and Clp as well as Vd of salicylate were smaller in adult females than in males of comparable age. Relative to nonpregnant adult females, Vd of salicylate in pregnant rats was larger but plasma t1/2 and Clp were unchanged. In all groups of rats studied, PCM decreased the plasma t1/2 and increased the Clp of salicylate; Vd was unchanged. Changes in salicylate pharmacokinetics were not due to any differences in serum protein-salicylate binding or to serum testosterone levels. Ovariectomy decreased the plasma t1/2 of salicylate but castration of male rats had no significant effect. Administration of testosterone to ovariectomized female rats exerted no significant effect on salicylate pharmacokinetics. It is concluded that the physiological state and the nutritional status can modify salicylate pharmacokinetics; in so far as the rat model reflects the human situation, these variables should be taken into account for a rational salicylate therapy.     

Pharmacokinetics of D,L-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) in pregnant rats at different stages of gestation and maternal-fetal disposition during late pregnancy

The pharmacokinetics of D,L-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an investigational anticonvulsant drug, was evaluated in nonpregnant and in pregnant rats on gestation day (GD) 7, 12, and 21 after an intraperitoneal (i.p.) dose of 50mg/kg. Maternal-fetal disposition in the GD21 group was also evaluated. In all groups, HEPP was rapidly absorbed and the disposition was well described by an open two-compartment kinetic model. The most pronounced effects of pregnancy on the kinetics of HEPP were observed at GD21 in which significant increases in the first-order hybrid disposition rate constants alpha and beta, with corresponding decreases in half-lives were observed. Gestation also affected the intercompartmental transfer rate constants k(12) and k(21), specially at GD12 and at GD21. These changes could be associated with the physiologic increases in blood flow and cardiac output of pregnancy. There was also a slight decrease in the apparent volume of distribution at GD21, and a progressive decrease in the clearance values normalized by the body weight. No other significant differences in kinetic parameters were observed. On GD21, HEPP rapidly transfers from maternal blood to fetuses, to reach concentrations in the placenta and fetuses slightly higher than those of the maternal plasma (fetal:maternal ratio ranging from 1.07 to 1.45). After equilibrium, the concentrations in maternal, placental, and fetal tissues decreased in parallel.     

Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat

Correlations between oral and intravenous (i.v.) doses of phenytoin, maternal plasma levels, and subsequent developmental toxicity were examined in the Sprague-Dawley rat. Oral administration of 150 to 1500 mg/kg and i.v. administration of 25 to 100 mg/kg phenytoin from gestational days (GD) 8 to 17 resulted in a dose-dependent increase in maternal death and toxicity [impaired motor function, decreased maternal weight gain (oral dose only)], embryolethality, and intrauterine growth retardation, in addition to significant increases in craniofacial (1125 mg/kg oral; 75 mg/kg i.v.) and urogenital (1125 mg/kg oral) malformations. Pharmacokinetic sampling in oral and i.v. groups on GD 8-9 and 16-17 revealed significant increases in maternal drug exposure over the treatment period, as evidenced by 2- to 3-fold increases in total plasma phenytoin (bound + free) half-life, area under the concentration curve, peak concentration (oral dose only), and decreases in clearance. These findings emphasize the importance of pharmacokinetics in the evaluation of phenytoin-induced developmental toxicity.     

The influence of age on salicylate pharmacokinetics in humans

The pharmacokinetics of salicylate after a single oral solution dose of 600 mg of sodium salicylate were investigated in 22 male subjects. Subjects were healthy nonsmokers and were not taking any regular medication. The plasma concentration and urinary excretion of salicylic acid and its metabolite, salicyluric acid, as well as the urinary excretion of salicyl glucuronides were determined. Urinary recovery essentially accounted for the administered dose and was not influenced by age, nor was the apparent oral clearance of salicylic acid. Assuming no presystemic elimination, it could be concluded that systemic availability is unaffected by age. An increase in the apparent volume of distribution, Varea, and a decrease in the maximum plasma salicylic acid concentration with age were observed. Renal clearance of salicyluric acid decreased significantly with age and was found to correlate significantly with creatinine clearance. The authors conclude that age does not have a major influence on salicylate disposition in healthy adult men.     

Dose-dependent pharmacokinetics of ibuprofen in the rat

The linearity of the pharmacokinetics of ibuprofen was examined in male Sprague-Dawley rats given iv bolus doses of 10, 20, and 50 mg/kg ibuprofen. Plasma and urine concentrations of ibuprofen and its two major metabolites, OH-ibuprofen and COOH-ibuprofen, were determined by HPLC and the binding of ibuprofen to plasma proteins was measured by an ultrafiltration technique. The systemic plasma clearance (CLtot) of ibuprofen was dose-dependent and decreased from 0.29 to 0.14 liter/hr/kg primarily as a result of a 65% decrease in the partial metabolic clearance to OH-ibuprofen while the average mean residence time (MRTtot) increased approximately 35% over the 10-50 mg/kg dosage range. Since there were no dose-dependent changes in the apparent steady state volume of distribution (Vss,tot), the mean harmonic half-life increased from 1.7-2.8 hr over the dosage range studied. The binding of ibuprofen to plasma proteins was relatively independent of concentration up to 90 mg/liter (mean free fraction approximately 5.5%), but became markedly concentration-dependent thereafter (free fraction up to 25.4% at 411 mg/liter). The mean recovery of total ibuprofen in the urine over 24 hours at 10 mg/kg was 62.1% and decreased by 24% and 40% at 50 and 20 mg/kg, respectively. This dose-dependent decrease in the percentage excreted in the urine was primarily due to a reduction in the recovery of OH-ibuprofen slightly offset by a small, but significant, increase in the urinary excretion of COOH-ibuprofen between 10 and 50 mg/kg. The apparent pharmacokinetic parameters based on free, unbound concentrations of ibuprofen were also dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)     

乙醇对苯妥英钠药代动力学的影响

目的 :观察乙醇对苯妥英钠药代动力学的影响。方法 :分别对8只家兔单用苯妥英钠和乙醇合用后苯妥英钠的药代动力学参数变化进行研究和比较 ,采用紫外分光光度法测定苯妥英钠的经 -时血药浓度 ,以“3p87”程序拟合药代动力学参数。结果 :合用乙醇后 ,苯妥英钠的AUC由 (4108 64±1039 98)ml/(L·min)降至 (1903 65±1003 40)mg/(L·min) ;T1/2(ke)由 (98 45±26 4)min降至 (82 84±25 5)min ;Vd 由 (0 3475±0 0360)L/kg升至 (0 6819±0 1901)L/kg ;CLs 由 (0 0026±0 0008)ml/(kg·min)升至(0 0062±0 0022)ml/(kg·min) ;Cmax 由 (29 0±2 94)mg/L降至 (16 0±5 9)mg/L。结论 :合用乙醇后 ,苯妥英钠的消除在体内明显加快     

Disposition of valproic acid in maternal, fetal, and newborn sheep. I: placental transfer, plasma protein binding, and clearance.

Separate 24-h maternal and fetal infusions of valproic acid (VPA) were administered to five pregnant sheep at 125 to 138 days gestation (term approximately 145 days) to determine maternal-fetal disposition. The pharmacokinetics of VPA were also investigated in five newborn 1-day-old lambs after a 6-h drug infusion. Plasma, urine, and amniotic and fetal tracheal fluid samples were analyzed for VPA using gas chromatography-mass spectrometry. During maternal drug infusion, the average steady-state fetal/maternal unbound VPA plasma concentration ratio was 0.81 +/- 0.09. Unbound maternal-to-fetal VPA placental clearance (69.0 +/- 20.2 ml/min/kg) was similar to that in the other direction (61.9 +/- 24.2 ml/min/kg); this indicates passive placental diffusion and intermediate placental permeability of VPA in sheep. Newborn unbound VPA clearance (0.66 +/- 0.28 ml/min/kg) was much lower than in the mother (5.4 +/- 2.7 ml/min/kg) or the fetus (62.1 +/- 22.4 ml/min/kg), and exhibited pronounced Michaelis-Menten characteristics. The elimination half-life of the drug was much longer in the newborn (18.6 +/- 2.6 h) relative to the mother (5.6 +/- 1.4 h) and the fetus (4.6 +/- 1.9 h). Thus, VPA elimination in newborn lambs is much slower as compared with adult sheep, a situation similar to that in humans. Plasma protein binding of VPA was saturable, with similar VPA binding capacities and affinities in maternal and fetal plasma. VPA was extensively displaced from binding sites in the newborn lamb during the first 1 to 2 days of life, possibly because of increased plasma free fatty acid concentrations at birth. Thereafter, newborn plasma appeared to have a similar VPA binding capacity but lower affinity compared with the mother and the fetus.     

Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

Purpose

We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.

Methods

We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.

Results

We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.

Conclusions

The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.     

Pharmacokinetics of nitroglycerin after parenteral and oral dosing in the rat

The pharmacokinetics of nitroglycerin was characterized in detail using venous plasma after different intravenous bolus doses (0.15-2.48 mg/kg), intra-arterial infusion (8.2 micrograms/min over 5 h), and oral doses (7-100 mg/kg). Venous plasma clearance was found to be approximately 650 mL/kg and was independent of the intravenous or intra-arterial dose. This confirmed earlier reports that the venous plasma clearance of nitroglycerin in rats exceeded the value of normal cardiac output. A terminal half-life of approximately 15 min was observed after high intravenous bolus doses of nitroglycerin. This slow disappearance phase was likely rate limited by redistribution of drug back into the plasma. The bioavailability of oral nitroglycerin (F) showed an apparent Michaelis-Menten dependency on dose. F was less than 5% at doses less than 20 mg/kg, but increased to a plateau of approximately 20% from 50-100 mg/kg. First-pass metabolism of nitroglycerin is thus apparently controlled by at least two systems (sites or enzymes). Coadministration of mannitol hexanitrate, a potential competitive inhibitor of first-pass metabolism, did not increase F.     

Kinetics of Phenytoin in Pregnant and Non-pregnant Rats

Abstract The plasma kinetics of phenytoin were studied in pregnant and nonpregnant rats after a single intravenous dose. The apparent volume of distribution was greater in the pregnant rats resulting in lower plasma concentrations in these rats within the first hour of injection. The beta half-life in pregnant rats (5.0 hours) was prolonged compared to the non-pregnant rats (2.2 hours). The plasma clearance values which take the altered volume of distribution into account, showed a smaller but still significant difference between the two groups of rats. This indicates a lower capacity of the pregnant rats to metabolize the drug.     

Diphenhydramine disposition in the sheep maternal-placental-fetal unit: determinants of plasma drug concentrations in the mother and the fetus

The objective of this study was to identify the important factors that determine plasma concentrations of diphenhydramine (DPHM) in the mother and the fetus after maternal as well as fetal steady-state drug administration. Inter-relationships were evaluated between maternal and fetal placental and nonplacental clearances, plasma protein binding, and steady-state plasma concentrations of DPHM among data obtained from 18 pregnant sheep during late gestation. The major determinant of plasma DPHM concentrations in the mother after maternal as well as fetal administration appears to be maternal plasma protein binding and maternal nonplacental clearance. In contrast, the major determinant of fetal plasma DPHM concentrations after maternal drug administration was the extent of fetal first-pass hepatic drug uptake from the umbilical vein. However, after fetal drug administration, the fetal plasma concentrations were related to the extent of fetal plasma protein binding and fetal placental and nonplacental clearances. The index of fetal-to-maternal placental drug transfer after fetal drug administration (steady-state maternal-to-fetal plasma concentration ratio) was related to steady-state fetal plasma unbound fraction and fetal placental and nonplacental clearance. However, this index was not related to the magnitude of the factors operating on the maternal side of the placenta such as maternal plasma protein binding and maternal nonplacental clearance. This might indicate a lack of complete equilibration of the unbound drug concentrations on the two sides of the placenta at the exchange site.