Differences In Systemic Clearance Research Articles

Effect of Obesity on Pharmacokinetics of Transdermal Fentanyl: Single-Center Retrospective Study and Animal Study

A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI > 25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5-25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CLtot) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (Fa) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (Fskin), calculated as F divided by Fa, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.

Pharmacokinetics of furosemide in thoroughbred horses subjected to supramaximal treadmill exercise with and without controlled access to water

BackgroundThe primary objective of this study was to assess the disposition of furosemide in Thoroughbred horses treated intravenously with 1 mg/kg of furosemide 4 and 24 h before supramaximal treadmill exercise without and with controlled access to water, respectively. Another objective was to determine whether furosemide was detectable in the plasma of horses after exposure to supramaximal treadmill exercise. Thoroughbred horses (n = 4–6) were administered single intravenous doses of 1 mg/kg of furosemide at 4 and 24 h before supramaximal exercise on a high-speed treadmill, with controlled and free access to water, respectively. Plasma furosemide concentrations were determined using liquid chromatography.ResultsFurosemide was detected in all the horses, regardless of whether they were treated 24 h or 4 h before excersice. In both treatment sequence groups of 2 horses, the concentration time profiles of furosemide during the first 4 h after its administration were relatively similar. The average maximum observed concentrations, AUC0–1.5h, and AUC0–3h, of both groups of horses were not different (p > 0.05). There were no significant differences in systemic clearance based on the geometric mean (95% confidence interval) (409 (347–482) mL/h/kg) for 4 h and 320 (177–580) mL/h/kg) for 24 h) between horses that were exercised 4- and 24-h post-furosemide administration. The plasma concentration of furosemide in all the horses fell below the limit of quantification (25 ng/mL) within 12 h after drug administration. In the group treated 24 h before exercise, none of the horses had detectable furosemide at the time of supramaximal treadmill exercise. In the group treated 4 h before exercise, furosemide was detected 1 h before and 2 h after supramaximal treadmill exercise in 4/4 and 3/4 horses, respectively. The mean AUC3-last h of both groups of horses were not different (p > 0.05).ConclusionsWater restriction did not exert any apparent effect on the disposition of furosemide. It remains to be determined, however, whether the attained plasma concentration of furosemide in combination with other controlled water access protocols have any direct or indirect pharmacological effect that may affect the athletic performance of the horse.

The Relative Bioavailability of the Calcium Salt of β-Hydroxy-β-Methylbutyrate Is Greater Than That of the Free Fatty Acid Form in Rats

Background:β-Hydroxy-β-methylbutyrate (HMB) supplementation has been demonstrated to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. The beneficial effects of HMB have been studied by using either the calcium salt, monohydrate, of HMB (CaHMB) or the free acid form (FAHMB). Objective:The present study was designed to compare the pharmacokinetics and relative bioavailability of the 2 forms of HMB administered as a liquid suspension in male Sprague-Dawley rats. Methods:CaHMB at 30, 100, and 300 mg/kg and equivalent doses of FAHMB at 24.2, 80.8, and 242 mg/kg were administered orally as a liquid suspension to male Sprague-Dawley rats. A single i.v. dose of 5 mg/kg CaHMB, corresponding to an equivalent dose of 4.04 mg/kg FAHMB, was also administered. Plasma concentrations of HMB were analyzed by liquid chromatography tandem mass spectrometry, and pharmacokinetic variables and relative bioavailability of the 2 forms of HMB were determined. Results:After oral administration, the area under the plasma concentration time curve (AUC) from time 0 to time t (0-t) and from time 0 to infinity (0-∞) and the maximum (peak) plasma concentration (Cmax) for CaHMB were significantly greater than for FAHMB, whereas the time to reach Cmax did not differ from that of FAHMB. The relative bioavailability of CaHMB was 49%, 54%, and 27% greater than that of FAHMB for the 3 respective oral doses tested. After i.v. administration, the AUCs 0-t and 0-∞ of the calcium salt were significantly greater than those of FAHMB. The relative bioavailability of CaHMB was 80% greater than that of FAHMB. The higher relative bioavailability of CaHMB may be attributable to its low systemic clearance compared with FAHMB. Conclusions:This study demonstrates the enhanced relative bioavailability of CaHMB compared with FAHMB. Further studies are warranted to understand the physiologic mechanisms contributing to the differences in systemic clearance.

Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo. Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR). Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89-128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients' sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time-plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup. No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

In vivo and in vitro characterization of ethyl methanesulfonate pharmacokinetics in animals and in human

Pharmacokinetics of ethyl methanesulfonate (EMS) were characterized in mice, rats and in cynomolgus monkeys with unlabelled and 14C-radiolabelled EMS by either quantification of unchanged EMS or the N-ethyl-valine haemoglobin (Hb) adduct. EMS was well absorbed and exhibited close to 100% oral bioavailability. EMS showed some species differences in systemic clearance (intermediate in mice, low in rats and monkeys) representing only 1–4% of the cardiac output. The volume of distribution (0.5–0.8 L/kg) was constant across species and corresponded to extracellular water. As a result of the species differences in clearance, the half-life ranged from 10 min in mouse (at low dose) to 5 h in monkey. The systemic exposure of free EMS and the levels of its Hb adduct increased nearly dose proportionately from 1 to 5 and 0.5 to 80 mg/kg, respectively. The persistence of the N-ethyl-valine Hb adduct was much longer than EMS itself, consistent with the long life span of haemoglobin. No species differences were evident for the binding of EMS to Hb in whole blood ex vivo as determined by the second order rate constants. Following administration of Viracept tablets of the contaminated production batches (to monkeys leading to EMS doses of 0.08–27 μg/kg, concentrations of ethyl-valine Hb adducts) were near or below the detection limit of the assay (0.043 nmol/g Hb).

Phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC)

14504 Background: Docetaxel is first-line standard treatment for metastatic HRPC. New combinations with targeted therapies may improve clinical responses. . Atrasentan is an endothelin receptor A (ETA) inhibitor with an IC50 in the pM range. Clinical studies suggest atrasentan delays time to disease progression, bone turnover markers and PSA kinetics. Methods: We conducted a Phase I/II trial of docetaxel and atrasentan to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and treatment response of this regimen. Patients were treated with docetaxel IV every 3 weeks at doses ranging from 60 to 75 mg/m2. Atrasentan was given orally at 10 mg daily starting on Day 3 and continuously thereafter. Initially, we defined DLT as grade IV neutropenia, but subsequently amended the protocol to redefine DLT as grade IV neutropenia lasting ≥ 7 days. Plasma PK evaluations were conducted for each drug when administered alone (Cycle 1 Day 1, 21) and together (Cycle 2 Day 1). Serial samples were evaluated by LC-MS and data were modeled using a standard, two-stage approach. Results: 18 patients were enrolled over 3 dose levels (9 at 60 mg/m2; 6 at 70 mg/m2 and 3 at 75 mg/m2) in the phase I portion and to date 9 more patients have been enrolled in a dose expansion cohort at a docetaxel dose of 70 mg/m2. Patient demographics include median age 69, PSA level 87.3 ng/ml, hemoglobin 12.7 g/dl, and KPS 90%. DLT, initially any grade IV neutropenia, was seen at every dose level, however no grade IV neutropenia has lasted ≥ 7 days and no MTD has been defined to date. Drug-related grade III/IV toxicities included only neutropenia (42%); grade I-II toxicities included fatigue, peripheral edema, and nausea. To date, 5 of 15 evaluable patients who have been treated with 70–75 mg/m2 of docetaxel and 10 mg of atrasentan demonstrate a sustained PSA response. Preliminary PK data in 11 patients show a mean docetaxel terminal half-life of 46 hr and systemic clearance of 55 L/hr. The median difference in systemic clearance between the cycles was 18% with values increasing in 67% of subjects. Conclusions: The combination of docetaxel and atrasentan appears to be well tolerated to date. The study is ongoing to more accurately determine safety, response and potential pharmacokinetic interactions. [Table: see text]

Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs

Astragaloside IV, a natural product purified from the Chinese medical herb Astragalus membranaceus (Fisch) Bge, is now being developed as a cardioprotective agent for treating cardiovascular diseases. The purpose of the present study was to examine in vivo pharmacokinetics and tissue distribution in both rats and dogs by using an established high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry quantitative detection method. Astragaloside IV showed moderate to fast elimination; the elimination half-life of astragaloside IV was 98.1, 67.2 and 71.8 min in male rats, and 34.0, 66.9 and 131.6 min in female rats at doses of 0.75, 1.5 and 3.0 mg/kg, respectively. There was no significant difference in systemic clearance at three dose levels, suggesting that astragaloside IV may have linear pharmacokinetic characteristics in rats within the dose ranges tested. The highest concentration of astragaloside IV was detected in the lung and liver. However, limited distribution to the brain, indicates that astragaloside IV may have difficulty penetrating the blood brain barrier. In addition, only about 50% of the parent astragaloside IV was recovered in both urine and feces. These results indicate that there was about 83% astragaloside IV binding to plasma protein and that the binding to the plasma is linear at the concentration range of 250–1000 ng/ml. As in rats, astragaloside IV may have linear pharmacokinetic characteristics in dogs within the dose ranges tested. Astragaloside IV was slowly cleared via hepatic clearance with a systemic clearance (CL) of about 0.004 l/kg/min. Based on the favorable pharmacokinetic properties in both rats and dogs, astragaloside IV warrants further investigation for the prevention of cardiovascular diseases.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague–Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague–Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration–time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.

Carboplatin pharmacokinetics following a single-dose infusion in sulphur-crested cockatoos (Cacatua galerita).

To determine the pharmacokinetics of carboplatin in sulphur-crested cockatoos, so that its use in clinical studies in birds can be considered. A pharmacokinetic study of carboplatin, following a single intravenous (IV) or intraosseus (IO) infusion over 3 min, was performed in six healthy sulphur-crested cockatoos (Cacatua galerita). Birds were anaesthetised and a jugular vein cannulated for blood collection. Carboplatin (5 mg/kg) was infused over 3 min by the IV route in four birds via the contralateral jugular vein, and by the IO route in two birds via the ulna. Serial blood samples were collected for 96 h after initiation of the infusion. Tissue samples from 11 organs were obtained at necropsy, 96 h after carboplatin administration. Total Pt and filterable Pt in plasma and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma data. The mean +/- SD for the Cmax of filterable Pt was 27.3 +/- 4.06 mg/L and in all six birds occurred at the end of the 3 min infusion, thenceforth declining exponentially over the next 6 h to an average concentration of 0.128 +/- 0.065 mg/L. The terminal half-life (T1/2) was 1.0 +/- 0.17 h, the systemic clearance (CI) was 5.50 +/- 1.06 mL/min/kg and the volume of distribution (Vss) was 0.378 +/- 0.073 L/kg. The extrapolated area under the curve (AUC0-x) was 0.903 +/- 0.127 mg/mL x min; the area extrapolated past the last (6 h) data point to infinite time averaged only 1.25% of the total AUC0-x. The kidneys had the greatest accumulation of Pt (7.04 +/- 3.006 microg/g), followed by the liver (3.08 +/- 1.785 microg/g DM). Carboplatin infusion in sulphur-crested cockatoos produced mild, transient alimentary tract signs and the Pt plasma concentration was similar whether carboplatin was given intravenously or intraosseously. Filterable plasma Pt concentrations for carboplatin persisted longer than for cisplatin, due mostly to the difference in systemic clearance between these drugs in sulphur-crested cockatoos. The distribution of tissue Pt after carboplatin administration was similar to that reported for cisplatin in sulphur-crested cockatoos. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of filterable Pt in the sulphur-crested cockatoo shares some features with the kinetics reported previously in other animals and human beings.

Genetic polymorphisms of the CYP3A5 and MDR-1 genes and effect of clarithromycin (CLAR) on midazolam (MDZ) pharmacokinetics

Objective CLAR significantly reduces the intravenous and oral clearance of MDZ. In this study, we investigate the possible role of the CYP3A5 and MDR-1 gene variants in this drug-drug interaction. Methods A retrospective analysis was done in 24 healthy volunteers who had received simultaneous administration of IV and oral MDZ before and after 7 days CLAR. CYP3A5*3 and MDR-1 G2677T alleles were determined by PCR. Results Five subjects had a CYP3A5*1 allele including one subject with a CYP3A5*1/*1 genotype. The baseline systemic clearance (31.1 ± 9.1 vs 30.4 ± 9.3 L/hr, p = 0.9) and oral clearance (165.4 ± 91.1 vs 113.8 ± 80.5 L/hr, p =0.2) of MDZ did not differ between CYP3A5 *1 and *3/*3 carriers, respectively. After CLAR treatment, there were no statistical significant differences in systemic clearance (17.2 ± 10.7 vs 10.9 ± 5.4 L/hr, p = 0.07) and percent change in oral clearance (74% vs 83%, p = 0.1) of MDZ between CYP3A5 *1 and *3/*3 carriers, respectively; however, oral clearance (49.6 ± 63.1 vs 15.0 ± 8.3 L/hr, p = 0.02) of MDZ and percent change in systemic clearance (45% vs 63%, p = 0.04) in CYP3A5*1 carriers were significantly higher than *3/*3 homozygotes. No difference in pharmacokinetics or extent of drug interaction was found between the MDR-1 genotypes. Conclusion These data suggest that people who possess a CYP3A5*1 allele are less susceptible to CYP3A inhibition by CLAR. Clinical Pharmacology & Therapeutics (2004) 75, P70–P70; doi: 10.1016/j.clpt.2003.11.264

A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics.

Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.

Disposition of propofol after medetomidine premedication in beagle dogs

SUMMARY Propofol by infusion was administered to 6 adult beagle dogs on 2 separate occasions. The dogs received either no premedication or 20 μg/kg im medetomidine 15 min before induction of anaesthesia, with propofol given at 7 mg/kg/min to permit tracheal intubation. After tracheal intubation the infusion rate was maintained for 120 min at 0.4 mg/kg/min in the non-premedicated, and 0.2 mg/kg/min in the premedicated dogs. The latter group received atipamezole 50 μg/kg im immediately at the end of the infusion. After induction of anaesthesia, a 7F balloon catheter designed for thermal dilution measurement of cardiac output was inserted via the right jugular vein. Blood propofol concentrations were measured by HPLC with fluorescence detection and kinetic variables calculated using non-compartmental moment analysis. The induction dose of propofol was 7.00 (sem 0.55) mg/kg in non-premedicated compared with 3.09 (0.25) mg/kg in premedicated dogs. There were differences in systemic clearance and mean residence time (MRTiv); 47.5 (6.2) ml/kg/min vs 29.0 (4.4) ml/kg/min (non-premedicated vs premedicated) and 132.3 (5.2) min vs 152.4 (3.1) min (P

Pharmacokinetics of amphotericin B in rats as a function of dose following constant‐rate intravenous infusion

Amphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague-Dawley rats were given different two-step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 +/- 0.33, 0.86 +/- 0.24, and 0.37 +/- 0.04 mL min-1 kg-1 for the low-medium and high-dose groups, respectively; p < 0.05). Signs of renal impairment were observed in the high-dose group, as documented by decreased creatinine clearance. Dose-dependent renal clearance may have been due either to nephrotoxicity associated with the high dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time-averaged values (based on the estimation of area under the plasma concentration-time profile). This suggests that clearance calculations from time-averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation of systemic clearance.

EFFECT OF I.V. ANAESTHESIA WITH PROPOFOL ON DRUG DISTRIBUTION AND METABOLISM IN THE DOG

We have studied the effect of i.v. anaesthesia with propofol in the emulsion (Intralipid) formulation on drug distribution and metabolism in six dogs using dual-route administration of propranolol as a model compound. Each dog was studied on two consecutive days: day 1 awake and day 2 during propofol anaesthesia (6 mg kg-1 followed by an infusion of 0.8 mg kg-1 min-1). Propofol anaesthesia was associated with reduced intrinsic clearance by 40% (P less than 0.05) but no significant difference in systemic clearance or hepatic plasma flow. Propofol produced marked changes in drug distribution; volume of distribution (Vss) of propranolol increased 54% from 82.5 (SEM 7.3) litre awake to 127.3 (27) litre during propofol anaesthesia (P less than 0.05). This change was accompanied by an increase (P less than 0.05) in the free fraction of propranolol from 8.5 (0.7) % in awake to 14.0 (0.7) % in propofol-anaesthetized dogs. The combination of the effects of both drug clearance and protein binding resulted in a 65% decrease in the intrinsic clearance of unbound drug (P less than 0.05). In contrast with the effects of propofol on drug distribution, infusion of Intralipid alone in another group of six dogs had no significant effects on drug distribution, protein binding or drug metabolism. We conclude that propofol is a modest inhibitor of drug metabolism, but has major effects on propranolol distribution, possibly by changing plasma protein binding.

Influence of lovastatin on the pharmacokinetics, toxicity and immunologic response of cyclosporine in the obese zucker rat

The combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug-free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre-treated with either oral lovastatin 2.5 mg kg-1 day-1 or propylene glycol vehicle for 1 week. Although no differences in renal function were observed in rat groups administered cyclosporine or lovastatin alone, there was a significant reduction in baseline creatinine clearance following combination therapy compared to placebo controls (70 +/- 18 vs 121 +/- 16 per cent of baseline; p less than 0.05). No differences in trough cyclosporine concentrations were observed between groups. Similarly, mean areas under the whole blood concentration-time profiles were not significantly different with or without concomitant lovastatin (61823 +/- 27295 vs 41470 +/- 10312 ng h ml-1; p = 0.13). No differences in systemic clearance or volume of distribution of parent cyclosporine were observed with combination therapy. Furthermore, lipid levels and T-lymphocyte activity were unchanged with the addition of lovastatin. Per cent increases in creatine kinase were significantly correlated with percentage drop in baseline renal function, suggesting the development of rhabdomyolysis. The present data support the interaction between cyclosporine and lovastatin observed clinically, resulting in acute renal dysfunction. Caution should be exercised in their combined use.

Aluminum bioavailability and disposition in adult and immature rabbits

Prolonged aluminum (Al) exposure produces neurobehavioral and skeletal toxicity. To further characterize the risk from Al exposure, lactating rabbits were administered iv (40 or 80 μmol/kg), po (4 or 20 mmol/kg), and sc (400 μmol/kg) doses of Al lactate on Days 10, 15, and 20 of lactation. Baseline pretreatment Al concentration averaged 138 ng/ml in serum and 710 ng/ml in milk. Individual baseline values were subtracted from posttreatment samples, and pharmacokinetic analysis was performed on these residual values. The high and low doses did not produce statistically significant differences in systemic clearance, half-life, or the apparent volume of distribution. The amount of aluminum in milk 24 hr after injection was estimated to be 2.4% of the iv and 3.3% of the absorbed sc dose. Systemic bioavailability of Al after low- (0.7 ± 0.5% x ± SD) and high-dose po Al (1.9 ± 1.7%) was not significantly different. Bioavailability of sc Al was 27 ± 7%. Rabbits receiving daily sc Al injections (400 μmol/kg) for 28 consecutive days demonstrated nonlinear kinetics. Preinjection serum Al concentrations and the area under the curves associated with the 7th dose were considerably greater than with the 1st dose. Further increases were seen with the 28th dose. Seven days after the last Al injection, 12% of the total Al injected was still in the region of the injections, indicating prolonged absorption. The bioavailability and disposition of Al were determined in 17- to 24-day old suckling rabbit offspring after iv (40 μmol/kg) and po (4 mmol/kg in water or milk) doses of Al lactate. Baseline pretreatment serum Al concentration averaged 119 ng/ml. Mean systemic clearance was comparable in offspring and adults, although the apparent volume of distribution was greater in offspring producing a longer half-life in the offspring. The limited distribution of Al into milk and poor GI absorption of Al support the observation that there is little risk of Al toxicity in suckling offspring of Al exposed nursing females.

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Furosemide disposition in cirrhosis

Furosemide disposition after rapid intravenous injection (80 mg) was studied in 10 normal healthy subjects and eight patients with cirrhosis and ascites. In the cirrhotic patients the elimination half-life was modestly longer (81.0 +/- 8.0 min and 60.2 +/- 5.8 min). This prolongation was not associated with a difference in systemic clearance (156 +/- 7 ml/min in normal and 142 +/- 16 ml/min in cirrhotic subjects), rather it was a reflection of alterations in furosemide distribution. The steady-state volume of distribution was increased from 8.5 +/- 0.4 l in the healthy subjects to 12.1 +/- 1.3 l in the cirrhotic subjects; estimation in terms of unbound drug indicated an approximately 50% smaller value in cirrhosis. These observations were quantitatively consistent with the increased percentage of furosemide in plasma in the unbound form in the patients (10.2 +/- 1.0%) compared to in the normal subjects (4.0 +/- 0.1%). The 24-hr percentage urinary recovery of unchanged drug (58.8 +/- 2.8% and 53.1 6.5%) and the glucuronide metabolite (17.8 +/- 1.5 and 21.3 +/- 3.4) were on the same order in the normal and cirrhotic groups. The lack of major effects of cirrhosis on furosemide disposition suggests that changes in furosemide diuretic efficacy in such patients is a result of altered dynamic factors rather than altered disposition.

Comparative pharmacokinetics of antipyrine (phenazone) in the baboon, cynomolgus monkey and rhesus monkey

The pharmacokinetics of antipyrine (phenazone) in 3 species of non-human primate have been evaluated following its intravenous administration at a dose level of 92 mg/kg. Mean peak plasma concentrations of antipyrine of 132, 137 and 155 μg/ ml in the rhesus monkey, the cynomolgus monkey and the baboon respectively were not observed until 5 min after intravenous injection. Thereafter, concentrations declined with an apparent half-life of elimination of 1.5–2 h. The time-course of plasma antipyrine concentrations was adequately described by a one-compartment open model and no notable differences in pharmacokinetic parameters utilising a 2-compartment open model were observed. Antipyrine was mainly distributed in total body water. The mean volume of distribution was equivalent to 88, 73 and 66% of body weight in the rhesus monkey, the cynomolgus monkey and the baboon, respectively. An analysis of variance of volumes of distribution, apparent half-lives of elimination and systemic clearances showed that there was a statistically significant species-related difference in systemic clearance ( P < 0.05) and volumes of distribution ( P < 0.01) which were lower in the cynomolgus monkey than in the other 2 species. The pharmacokinetics of antipyrine in the non-human primate are more similar to those of other laboratory animal species than to those of humans.