Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo interaction of the enantiomers of disopyramide in human subjects

Disopyramide, an antiarrhythmic agent, is marketed as a racemic mixture of two enantiomers. The racemic drug has unusual pharmacokinetic properties because of its concentration-dependent binding to plasma proteins in the therapeutic plasma concentration range. This study examined, in healthy subjects, the individual pharmacokinetic properties of both total and unbound d- and 1-disopyramide in plasma after intravenous administration of each enantiomer separately (1.5 mg/kg). Also investigated is the pharmacokinetics of total d- and 1-disopyramide in plasma after intravenous administration of a pseudoracemate. Both d- and 1-disopyramide are found to exhibit concentration-dependent binding to plasma proteins, with d-disopyramide being more avidly bound at lower concentrations. The stereoselective, concentration-dependent binding to plasma proteins resulted in distinct pharmacokinetic properties when the enantiomers were given together as the pseudoracemate. d-Disopyramide had a lower plasma clearance and renal clearance, a longer half-life, and a smaller apparent volume of distribution than 1-disopyramide. However, when the enantiomers were administered separately, there were no differences in the clearance, renal clearance, and volume of distribution between enantiomers calculated from either total or unbound drug concentrations. The results reveal an important pharmacokinetic interaction between the enantiomers of disopyramide when given as a racemic mixture, which may be dose-dependent and is not apparent upon administration of the enantiomers separately.     

Stereoselective pharmacokinetics of disopyramide enantiomers in man

The plasma protein binding and pharmacokinetics of S(+)-disopyramide and R(-)-disopyramide following infusions of 100 mg were compared in five healthy human volunteers. The binding of S(+)-disopyramide was higher than that of R(-)-disopyramide at similar unbound concentrations in all subjects. The association constant characterizing the interaction between plasma protein and the S(+)- and R(-)-enantiomers was 17.1 X 10(5) M-1, and 7.68 X respectively. The unbound clearance and half-life of S(+)-disopyramide averaged 604 ml/min and 3.67 hr, respectively, and differed from that of R(-)-disopyramide, which averaged 401 ml/min and 4.62 hr, respectively. Both enantiomers appear to undergo active tubular secretion. The unbound renal clearance of the S(+)- and R(-)-enantiomers averaged 338 and 182 ml/min, respectively (p = 0.05). The unbound steady-state volume of distribution of S(+)- and R(-)-disopyramide averaged 172 and 141 liters, respectively (p = 0.14). The renal clearance of the mono-N-dealkylated metabolite of disopyramide following the administration of S(+)- and R(-)-disopyramide averaged 345 and 170 ml/min, respectively (p less than 0.05).     

Pharmacokinetics of postoperative intravenous indomethacin in children

The disposition of indomethacin was studied in children aged one to four years. Indomethacin 0.35 mg/kg was administered as an intravenous infusion during 15 min. Venous blood samples were collected until 24 hr after infusion. Serum indomethacin was determined with gas chromatography. Using a non-linear regression analysis, the individual data were fitted by a two-compartment open mammillary model with central elimination. Calculated pharmacokinetic parameters were (mean +/- SD); alpha half-life 25.2 +/- 11.3 min; beta half-life 366 +/- 295 min; steady-state volume of distribution 0.74 +/- 0.75 l/kg; volume during elimination phase 1.53 +/- 1.27 l/kg; total body clearance 3.2 +/- 1.7 ml/min./kg. Accordingly, with respect to the pharmacokinetics of indomethacin, children seem to mature early, not later than at the age of one year.     

Deuterium isotope effect on the toxicokinetics of monomethylamine in the rat

The single-dose toxicokinetics of monomethylamine has been characterized in the rat by HPLC assay of serial blood samples. Biphasic first-order elimination was observed following an iv bolus dose of 19 mumol/kg with a terminal half-life of 19.1 +/- 1.3 min (mean +/- SE, N = 4). The apparent steady state volume of distribution, systemic blood clearance, and renal blood clearance were 1.21 +/- 0.09 liter/kg, 53.4 +/- 3.5 ml/min/kg, and 5.72 +/- 0.53 ml/min/kg, respectively. The administration of an intragastric dose permitted the calculation of the systemic bioavailability of monomethylamine as 69 +/- 3%. Duplicate experiments using the structural analogue with deuterium atoms substituted for hydrogens on the methyl group revealed a much slower elimination of the compound, although ultimately, 5 times as much was excreted unchanged in the urine. Isotope effects calculated as the ratios of terminal half-life, systemic blood clearance, and systemic bioavailability were 1.9, 2.2, and 1.8, respectively.     

Stereoselective differences in propranolol disposition in female Sprague-Dawley and Dark Agouti rats.

Although genetic constitution is recognized as an important factor in drug elimination, there is still only a modest amount of information about its impact on stereoselective drug disposition. To examine how strain differences in cytochrome P-450 expression may affect stereoselective drug elimination, the disposition of R- and S-propranolol was examined in female Sprague-Dawley (SD) and Dark Agouti (DA) rats. The half-life of R-propranolol was increased and its apparent oral clearance decreased significantly in DA rats relative to the SD strain [85 +/- 41 min (DA) vs. 26 +/- 10 min (SD) and 0.020 +/- 0.014 liter/min/kg (DA) vs. 0.31 +/- 0.14 liter/min/kg (SD)], respectively. Strain differences in S-propranolol half-life and apparent oral clearance also were observed, but were not as marked [97 +/- 36 min (DA) vs. 52 +/- 35 min (SD) and 0.20 +/- 0.13 liter/min/kg (DA) vs. 0.70 +/- 0.68 liter/min/kg (SD)], respectively. Due to a more pronounced effect of rat strain on the disposition of R-propranolol, the stereoselective S-/R- oral clearance ratio for propranolol was also strain-dependent [10 +/- 3 (DA) vs. 2.1 +/- 0.9 (SD)]. These differences could not be accounted for by propranolol stereoselective plasma protein binding or by a difference in the blood/plasma ratio for R- or S-propranolol in these separate strains. This represents one of the few examples where an increase in stereoselective drug disposition has been observed due to strain differences that diminish drug elimination.     

Gentamicin disposition in young and elderly patients with various degrees of renal function

The effect of aging on the total body clearance, volume of distribution, and half-life of gentamicin was examined in 99 febrile patients with various degrees of renal function. In the 50 patients who were 18 to 64 years old, clearance of gentamicin was 79.0 +/- 27.0 mL/min (mean +/- standard deviation), creatinine clearance was 98.6 +/- 33.3 mL/min, volume of distribution was 0.242 +/- 0.077 L/kg, and half-life was 2.63 +/- 0.90 hours. In the 49 patients who were 65 to 90 years old, these values were 36.9 +/- 16.3 mL/min, 51.2 +/- 21.2 mL/min, 0.244 +/- 0.102 L/kg, and 5.80 +/- 4.13 hours. Significant differences were observed between the two groups for all parameters except volume of distribution. Linear regression revealed good correlations between the disposition characteristics (clearance and elimination-rate constant) of gentamicin and age as well as creatinine clearance. However, there was no apparent relationship between the ratio of gentamicin clearance to creatinine clearance and age (r = .0731). These findings suggest that the disposition of gentamicin is independent of age but dependent on renal function.     

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.     

Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2-16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0-5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0-6 ml/min). In ACRF patients, the half-life of ornidazole was 10.8 +/- 1.4 h, the total plasma clearance 46.3 +/- 2.3 ml/min and the volume of distribution 0.73 +/- 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/- 5% and the dialysis clearance 64 +/- 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/- 0.4 ml/min and in 48 h 6.0 +/- 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half-life of ornidazole was 11.8 +/- 0.8 h and total plasma clearance was 48.3 +/- 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end-stage renal disease, the half-life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra-renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session.     

Disposition of guanadrel in subjects with normal and impaired renal function

The disposition of a single 25 mg oral dose of guanadrel was evaluated in 22 subjects with various degrees of renal function. The terminal elimination half-life was significantly prolonged in subjects with a creatinine clearance (ClCr) less than 30 mL/min/1.73 m2 (19.2 +/- 16.8 h) compared to 3.7 +/- 1.9 h in subjects with a ClCr greater than 80 mL/min/1.73 m2. Apparent total body clearance (Clp/F) was also progressively lower in the patients with decreased renal function and the decline was significantly correlated with ClCr (Clp/F = 0.0294 + 0.0236 Clcr, r = 0.74, P = 0.002). Renal clearance and apparent nonrenal clearance also declined as creatinine clearance decreased, and both were significantly correlated with the observed ClCr. Apparent volume of distribution averaged 11.5 +/- 8.9 L/kg and did not differ in patients with decreased renal function compared to those with normal renal function. Thus, the disposition of guanadrel is significantly altered in the presence of renal insufficiency and dosage adjustments may be necessary, especially in patients with ClCr less than 50 ml/min.     

Pharmacokinetics of ivermectin administered intravenously to cattle

Ivermectin, a macrocyclic lactone disaccharide antiparasitic agent, was administered intravenously to six young calves (one bull, five steers) as a bolus dose of 200 micrograms/kg. The disposition kinetics of ivermectin in cattle can be described by a three-compartment open model with elimination from the central compartment. Compartmental analysis yielded mean parameters as follows: terminal elimination rate constant (beta) = 0.258 d-1, biological half-life (t 1/2 beta) = 2.7 d; apparent volume of distribution of the central compartment (Vd1) = 0.45 L/kg; apparent volume of distribution at steady state (Vdss) = 2.4 L/kg. The area under the plasma concentration-time curve (AUC) was 254 ng X d/mL. Noncompartmental parameters, obtained by utilizing statistical moment theory, mean residence time (MRT), clearance (CL), and Vdss were calculated to be 2.8 d, 0.79 L/kg X d, and 2.2 L/kg, respectively.     

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].     

Pharmacokinetics and efficacy of pirmenol hydrochloride in the treatment of ventricular dysrhythmia

Pirmenol hydrochloride (CI-845), a new antiarrhythmic agent available for both oral and intravenous administration, was given to seven patients with chronic ventricular dysrhythmia in an open-label fashion. After intravenous infusion of 150 mg over 30 min, the mean (+/- SD) peak plasma concentration achieved was 2.14 +/- 0.75 microgram/ml. The terminal elimination half-life, the volume of the central compartment, and the total body clearance averaged 6.5 h, 0.70 +/- 0.36 L/kg, and 3.0 +/- 2.6 ml/min/kg, respectively. After a single 150-mg oral dose, the peak plasma concentration of 1.3 +/- 0.55 microgram/ml was achieved 1 to 3 h after dosing. The mean apparent elimination half-life was 7.6 h. An estimated absorption lag time ranging from 14 to 37 min was observed in all but one patient. The mean absolute bioavailability for the oral dose was 87%. Dysrhythmia data were available in six patients. Complete (100%) suppression of ventricular ectopic beats occurred in four patients for 1/2 to 15 h after intravenous infusion, and in three patients for 7 to 25 h after oral dose. This suppression occurred with a plasma pirmenol level as low as 0.4 microgram/ml. No significant side effects were observed.     

Prazosin disposition in young and elderly subjects.

1 The disposition of prazosin following oral and intravenous administration has been studied in seven young and seven elderly men, all of whom were in good health and living independently in the community. 2 The elimination half-life (min) of prazosin was 123 +/- 19.4 (s.d.) in the young and 194 +/- 36 in the elderly (P less than 0.01). 3 Clearance (ml min-1 kg-1) was 3.94 +/- 0.73 in the young and 3.53 +/- 1 in the elderly (P greater than 0.1). Volume of distribution at steady state (1 kg-1) was 0.63 +/- 0.14 in the young and 0.89 +/- 0.26 in the elderly (P less than 0.05). 4 The absolute bioavailability of orally administered prazosin was 0.68 +/- 0.17 in the young and 0.48 +/- 0.16 in the elderly (P less than 0.05). 5 The significant increase in prazosin half-life in the elderly results from an increased volume of distribution, not from decreased clearance. 6 Gastrointestinal absorption of prazosin decreases in old age.     

Meperidine pharmacokinetics following intravenous, peroral and buccal administration in beagle dogs

The pharmacokinetics of meperidine was studied in Beagle dogs following intravenous, peroral and buccal administration of a meperidine hydrochloride solution. The elimination half-life after I.V., P.O. and buccal routes was 0.75 +/- 0.14 hours, 0.93 +/- 0.18 hours and 0.36 +/- 0.10 hours, respectively. The volume of distribution and total clearance following I.V., P.O. and buccal administration were 2.41 +/- 0.34 L/kg and 42.5 +/- 8.9 ml/min/kg, 2.84 +/- 1.24 L/kg and 34.6 +/- 7.8 ml/min/kg, 1.01 +/- 0.52 L/kg and 34.7 +/- 8.0 ml/min/kg, respectively. The absolute bioavailability after P.O. and buccal administration was 11.0 +/- 6.8% and 11.9 +/- 6.6%, respectively. This paper discusses the observed low bioavailabilities on hypothesis of hepatic and lung first-pass effect. A hypothesis is presented to explain the delayed onset of absorption following buccal administration.     

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half-life was 27.3 +/- 1.3 h in males, 27.7 +/- 1.5 h in females in the follicular phase and 29.6 +/- 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/- 2.7 ml/min, 58.2 +/- 3.3 and 55.8 +/- 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 +/- 2.3 and 31.2 +/- 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/- 4.6 and 45.6 +/- 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/- 0.1%) to females in the luteal phase of the cycle (12.4 +/- 0.5%) to females using OC-steroids (13.5 +/- 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (Cli = 323 +/- 30 ml/min in females using OC-steroids, 530 +/- 37 ml/min in males and 459 +/- 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.     

Disposition of famotidine in renal insufficiency

The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30-60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10-30 mL/min); Group 3, end-stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72-hour period. Plasma concentration-time data demonstrated biexponential decay. The terminal elimination half-life was prolonged in Group 3 (18.6 +/- 5.7 hr) compared with Groups 1 (9.3 +/- 2.3 hr) and 2 (9.7 +/- 1.7 hr), P less than .05. Steady-state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLp) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLp correlated well with CLCR (CLp = 1.59 CLCR + 33.8, r = 0.830, P less than .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.     

Atenolol inhibits the elimination of disopyramide

The effect of atenolol on the total elimination of disopyramide and its main dealkylated metabolite was studied in 6 patients and 3 volunteers. During administration of 50 mg atenolol b.i.d. the clearance of disopyramide decreased significantly (p less than 0.02) from 1.90 +/- 0.71 (mean +/- SD) to 1.59 +/- 0.68 ml/kg/min, while its half-life, concentration of the metabolite, and the volume of distribution remained unchanged. The reduction in the clearance of disopyramide by atenolol might contribute to the alleged pharmacodynamic interaction between disopyramide and beta-blocking drugs.     

Pharmacokinetics of lithium in the elderly

The disposition and elimination of lithium was examined in nine female geriatric patients (aged 67 to 80 years) maintained on lithium carbonate as a once daily dose (300 to 600 mg) for the treatment of recurrent depression. Following the morning lithium dose (0.21 +/- 0.06 mmol/kg/day, mean +/- standard deviation), a peak steady state serum concentration of 0.83 +/- 0.25 mmol/liter was achieved at 2.2 +/- 1.2 hours. The mean distribution half-life (alpha-t1/2) was 2.7 +/- 1.2 hours, with distribution being complete at 10.6 +/- 3.0 hours. The mean terminal elimination half-life (beta-t1/2), the mean apparent oral clearance (Cl), and the mean apparent volume of distribution (Varea) were 26.9 +/- 5.5 hours, 15.6 +/- 4.0 ml/min, and 0.64 +/- 0.16 liter/kg, respectively. Compared to a younger adult cohort (35 +/- 10 years), the lithium Cl and Varea were significantly reduced and the alpha- but not beta-t1/2 prolonged in the elderly (p less than 0.05). Based on these pharmacokinetic differences, geriatric patients may require one-third to one-half less lithium than younger adults. The 12-hour standard serum lithium concentration remained a value of minimal intersubject variability when lithium was administered once daily. However, the therapeutic concentration range based on this 12-hour standard serum lithium concentration needs to be redefined for the prophylaxis of unipolar disorders in the elderly.