Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock.

Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of bacteria. Microdialysis catheters were placed into the peritoneal space during surgery. Meropenem concentrations in plasma and in PF were analyzed using compartmental modeling. Meropenem areas under the concentration-time curve were lower in PF than in plasma (average ratio, 73.8+/-15%) because of degradation confirmed ex vivo. Compartment modeling with elimination from a peripheral compartment described the data adequately, and was used to simulate steady-state concentration profiles in plasma and PF during various dosing regimens. At the currently recommended dosing regimen of 1 g infused over 20 min every 8 h, PF concentrations of meropenem in patients with severe peritonitis associated with septic shock reach values sufficient for antibacterial effects against susceptible, but not always against intermediately susceptible, bacteria.

Microdialysis studies of the middle ear distribution kinetics of amoxicillin in the awake chinchilla.

This work was performed to develop an experimental animal model for the study of antibiotic drug distribution into middle ear fluid (MEF) and to evaluate its relevance and significance to the clinical treatment of otitis media (OM). Chinchillas were assigned to normal or infected ear groups after Eustachian tube obstruction (ETO) or direct trans-bullar inoculation with type 3 Streptococcus pneumoniae. Following survival surgery to implant microdialysis (MD) probes in the jugular vein and middle ear (ME), amoxicillin was given intravenously (iv) as a bolus or infusion. Drug concentrations in blood and MEF were continuously monitored by microdialysis. The measured concentrations were corrected for probe recovery by simultaneous retrodialysis. Multiple MEF and blood sampling was also performed to validate the animal model and MD sampling technique. Bacterial infection was successfully induced 3-7 days after the inoculation, whereas the control group gave negative bacterial culture results. The beta-lactam antibiotic, amoxicillin, exhibited an elimination half-life of 0.33+/-0.23 h (n = 9) in chinchilla blood, 1.46+/-0.50 h (n = 5) and 1.75+/-0.84 h (n = 4) in MEF of normal and infected ears (p = 0.6), respectively. MEF-to-blood amoxicillin concentration ratios at steady state following iv infusion were 0.26+/-0.06 (n = 5) and 0.28+/-0.11 (n = 4) for normal and infected ears (p = 0.7), respectively. MD allows continuous monitoring of drug concentration-time profiles in blood and MEF in an awake chinchilla model. The concentrations measured by MD were validated by direct sampling. The ratio of the area under the curve (AUC) of drug concentration in MEF versus time to that in blood after iv bolus doses was less than unity, as was the steady-state concentration ratio following constant-rate iv infusion, suggesting an active transport mechanism was involved in the efflux of amoxicillin from the ME of chinchilla. The results of studies involving infected ears were not significantly different from those in normal ears in terms of amoxicillin distribution across the ME mucosal membrane after systemic administration.

Microdialysis in the study of drug transporters in the CNS.

Quantitative microdialysis in the central nervous system (CNS) has recently provided evidence for the existence of transporters as they relate to the brain distribution of a variety of drugs. Support for the existence of drug transporters in the blood-brain barrier (or in the blood-CSF barrier) comes from investigations that have found: unbound drug concentrations in brain fluids that are lower than corresponding levels in plasma; saturability of transport clearances across the blood-brain barrier and; the regulation of transport by putative inhibitors. Additional confirmatory evidence for the existence of active transport or carrier-mediated processes has also been derived from models that relate observed drug levels in the CNS with those in plasma or blood. The conclusion that reduced drug levels in brain fluids generally indicate the existence of active efflux transport is questioned. In the case of relatively polar compounds with modest blood-brain barrier permeability, lower unbound concentrations in brain may be a consequence of dilution by turnover of brain fluids. This review summarizes recent reports (grouped by class of compounds) where investigators have used microdialysis to examine the distribution of therapeutic agents to the CNS, and have reached conclusions regarding the functional presence of drug transporters in the brain.

Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers.

OBJECTIVES: To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3beta-acetoxyandrost-5-ene-7,17-dione) given orally. DESIGN: A randomized, double blind, placebo-controlled, escalating dose study. SETTING: The Chicago Center for Clinical Research. PARTICIPANTS: Twenty-two healthy men. STUDY METHOD: The participants received placebo (n = 6) or 3-acetyl-7-oxo-DHEA (n = 16) at 50 mg/d for 7 days followed by a 7-day washout; 100 mg/d for 7 days followed by a 7-day washout; and 200 mg/d for 28 days. OUTCOME MEASURES: Safety parameters, evaluated at each dose level, included measurement of total testosterone, free testosterone, dihydrotestosterone, estradiol, cortisol, thyroxin and insulin levels. Analyses for 7-oxo-DHEA-3beta-sulfate (DHEA-S), the only detectable metabolic product of the administered steroid, were conducted on plasma drawn from all subjects at 0.25, 0.5, 1, 2, 4, 6 and 12 hours after the final 100 mg dose of 3beta-acetyl-7-oxo-DHEA. RESULTS: There were no differences in the clinical laboratory values or in reported minor adverse experiences, between treatment and placebo groups. In general, blood hormone concentrations were unaffected by the treatment with 3beta-acetyl-7-oxo-DHEA and remained within the normal range. No changes in vital signs, blood chemistry or urinalysis occurred during treatment with 3beta-acetyl-7-oxo-DHEA compared to placebo. The administered steroid was not detected in the blood but was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose. This steroid sulfate did not accumulate; plasma concentrations 12 hours after the 3beta-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 mg/d dose were 15.8 and 16.3 microg/L respectively. The mean time to peak plasma level of 7-oxo-DHEA-S was 2.2 hours; the mean half life was 2.17 hours. The apparent clearance averaged 172 L/h, and the apparent mean volume of distribution was 540 L. CONCLUSION: These results indicate that 3beta-acetyl-7-oxo-DHEA is safe and well tolerated in normal healthy men at doses up to 200 mg/d for 4 weeks.

Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs.

Modification of recombinant human interleukin-2 (IL-2) with polyethylene glycol (PEG-IL-2) decreases clearance and might favor absorption into the lymphatics, due to its increased molecular weight. In the present study, we compared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshire pigs. The IL-2 regimens were i.v. bolus (0.1-1.6 x 10(6) I.U., MIU/kg), 15-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1-3.0 MIU/kg). The PEG-IL-2 doses were 15-min i.v. infusion (0.01 MIU/kg) or s.c. bolus (0.01-0. 10 MIU/kg). Lymph and plasma data were analyzed using noncompartmental methods and NONMEM. Bioavailability of IL-2 was route- and dose-dependent. Bioavailability of i.v. bolus doses of >/=0.16 MIU/kg was complete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavailability was 28 and 42%, respectively. Noncompartmental and NONMEM estimates of clearance and volume of distribution at steady state agreed: 300 ml/h/kg and 570 ml/kg, respectively, for IL-2. The ratio of the area under the curve in lymph and plasma increased from 0.67 to 3.4 when comparing i.v. and s.c. routes, and the s.c. delivery advantage (ratio of dose-normalized ratio of the area under the curve in lymph after s.c. and i.v. administration) was 6.6 to 16. For PEG-IL-2, bioavailability was 100%, clearance was 5.9 ml/h/kg, and volume of distribution at steady state was 370 ml/kg. The ratio of the area under the curve in lymph and plasma increased from 0.33 (i.v.) to 1. 2 (s.c.), and the s.c. delivery advantage was 3.8. Subcutaneous dosing would be favored over i.v. dosing, and IL-2 would be favored over PEG-IL-2 to maximize lymph and minimize plasma exposure. Because IL-2 efficacy may be related to lymph concentrations, dosing regimens can now be designed to test this hypothesis.

A partial area difference analysis for estimating elimination rate constants and distribution volumes of metabolites.

The true elimination rate constant of a metabolite is calculated using a partial area difference analysis. A linear pharmacokinetic model which describes clearances of parent and metabolite is developed. The model makes no restrictions on the route of administration of the parent but requires time-invariant kinetics for both parent and metabolite. Carbamazepine (CBZ), an antiepileptic, is metabolized to the 10,11-epoxide (CBZE), which is further hydrated to the trans-dihydrodiol (CBZD). Plasma data of the metabolites after a 200-mg single oral dose of Tegretol chewable tablets is used to demonstrate the applicability of the method. Elimination rate constants calculated using partial area analysis are 0.087 +/- 0.015 (h-1) and 0.056 +/- 0.014 (h-1) for CBZE and CBZD, respectively. These correspond to an average half-life of 8.0 h for CBZE and 12.4 h for CBZD, which suggest elimination-rate-limited disappearance of CBZD. The elimination rate constants for CBZE and CBZD calculated using partial areas are comparable to those in the literature determined after oral administration of CBZE. Volumes of distribution of CBZE and CBZD are also estimated to be 0.57 +/- 0.11 L/kg and 0.76 +/- 0.24 L/kg, respectively. The higher values observed with CBZD volumes of distribution are attributed to the higher plasma free fraction of the diol relative to CBZE.

Microdialysis studies of the distribution of stavudine into the central nervous system in the freely-moving rat.

PURPOSE: To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. METHODS: Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method. The CNS distribution of d4T was investigated during iv and intracerebroventricular (icv) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. RESULTS: During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 +/- 0.06 and 0.49 +/- 0.12, respectively (n = 15). During icv infusion, the steady-state d4T concentrations in the brain ECF were 23-fold higher than those during iv infusion, whereas its steady-state plasma levels were about the same for these two routes. Coadministration of AZT with d4T did not alter their respective brain distribution and systemic clearance at the concentrations examined. More importantly, the steady-state brain ECF/plasma and CSF/plasma concentration ratios of d4T were about 2-fold higher than those of AZT (0.15 +/- 0.04 and 0.25 +/- 0.08) determined in the same animals. CONCLUSIONS: d4T readily crosses the blood-brain barrier (BBB) and blood-CSF barrier. An active efflux transport system in the BBB and blood-CSF barrier may be involved in transporting d4T out of the CNS. Direct icv administration of d4T can be used to enhance its brain delivery. Moreover, d4T exhibits a more favorable penetration into the CNS than AZT and therefore may be useful in the treatment of AIDS dementia complex.

Bioavailability and pharmacokinetics of intravenously and orally administered allopurinol in healthy beagles.

OBJECTIVES: To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. ANIMALS: 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. PROCEDURE: In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined. RESULTS: Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. CONCLUSIONS: Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food. CLINICAL RELEVANCE: A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of > 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding.

Application of microdialysis in pharmacokinetic studies.

The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are being found in a variety of peripheral tissue types, e.g. skin, muscle, adipose, eye, lung, liver, and blood, and these are considered as well. Given the rising interest in this technique, and the ongoing attempts to adapt it to pharmacokinetic studies, it is clear that microdialysis sampling will have an important place in studying drug disposition and metabolism.

Kinetics of subcellular distribution of compounds in simple biosystems and its use in QSAR.

An explicit expression describing the kinetics of distribution and, in some cases, biological activity in drugs and other anthropogenic chemicals in a four-compartment system consisting of a catenary chain of alternating aqueous and lipoid phases is derived. Substitution of the transport rate parameters by their appropriate relations to the reference partition coefficient converts the kinetic equations into the quantitative structure-time-activity relationship (QSTAR) or its fixed-time equivalent, QSAR. The resulting expression describes satisfactorily the published data on antibacterial activity of n-alkyl amines as a function of their hydrophobicity. The hydrophobicity-activity profile consists of two or three smoothly connected linear parts. The model can be used in drug design, pharmacokinetics, and toxicology for description of the distribution of compounds in simple biosystems and in environmental sciences to predict the fate and effects of anthropogenic chemicals in ecological systems.

Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis.

EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marked CNS activity, in that it is a potent neuroprotector in models of cerebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of its high degree of ionization at physiologic pH, one would not expect appreciable brain uptake of EAB 515 across tight junctions of the blood-brain barrier. This is in contrast to its pharmacologic effect as well as brain/plasma ratios measured during systemic administration in rats. These observations lead us to investigate other transport pathways that might account for its brain uptake. Such mechanistic information is imperative in rational drug delivery and drug design strategies. Upon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-fold higher than those observed following intravenous administration, when normalized for the dosing rate. This increased distribution into the brain, based upon the route of administration, suggests the transport of drug directly between the cerebrospinal fluid and the brain extracellular space. The parameters of the model that adequately describes the data obtained from the two routes of administration in individual animals were estimated. The clinical significance of these results is in the use of intracerebroventricular administration for enhanced brain delivery of hydrophilic drugs that poorly cross the blood-brain barrier.

Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid.

The elimination of zidovudine (AZT) from cerebrospinal fluid (CSF), its distribution from CSF to brain tissue, and its transport from brain extracellular fluid (ECF) to plasma were studied during intracerebroventricular (i.c.v.) infusion in unanesthetized rabbits. The effect of probenecid (PBD) on these transport processes was also studied. The concentration of AZT in brain ECF was measured by microdialysis with retrodialysis calibration for in vivo recovery. Plasma and CSF were sampled and analyzed for AZT and PBD using HPLC. The elimination of AZT from CSF showed nonlinear characteristics as the i.c.v. infusion rate was increased to 1 mg/h kg. The estimated maximum transport capacity and dissociation constant were 3.5 micrograms/min kg and 127 micrograms/mL, respectively. The total linear elimination clearance from CSF was 0.0073 mL/min kg. The spatial distribution of AZT in brain during i.c.v. infusion was simulated using a mathematical model which describes diffusive solute transport in brain ECF and efflux across the blood-brain barrier. This analysis yielded a brain to plasma efflux rate constant of 0.040/min. This parameter and the elimination clearance from CSF decreased significantly by the end of an 8-hour period during which PBD was infused intravenously at a rate of 15 mg/h kg.

High-performance liquid chromatographic analysis of (S)-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (EAB 515) in brain and blood microdialysate (on-line) and in plasma ultrafiltrate of freely moving rats.

(S)-alpha-Amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (EAB 515, I), a competitive antagonist of the N-methyl-D-aspartate receptor, has significant pharmacological activity in the central nervous system (CNS). An extremely sensitive and selective analytical method was developed for the simultaneous analysis of I and its hydroxylated analog (RDC, II) in the microdialysate (MD) and plasma ultrafiltrate (UF) of rats. Microdialysis was used for in vivo sampling of unbound drug in the CSF, cortical extracellular fluid and in the blood of freely moving rats. Compound II was used for retrodialysis-based in vivo calibration of microdialysis probes to estimate the recovery of I. Compound I, being extremely hydrophilic with a high degree of ionization at the physiological pH of 7.4, has limited access to the brain regions. This, combined with its low microdialysis recovery, made the estimation of low brain concentrations of I a challenge. The analytes in MD and UF were separated (within 5 min) by reversed-phase HPLC on a 250 x 4.6 mm I.D. Maxsil 5 microns RP-2 column, and fluorescence of the eluent was monitored at 255 nm (lambda ex) and 320 nm (lambda em). A 0.09% (v/v) aqueous solution of trifluoroacetic acid (1 ml/min) was used as the mobile phase. The response for I in MD and UF samples was linear from 5 to 2000 ng/ml and from 20 to 10,000 ng/ml, respectively. The between-run (n = 6) and within-run (n = 3) variability of the assay was < 15%. Plasma-protein binding of I (fu = 0.68) was determined to be linear from 0.1 to 10 micrograms/ml. The analytical sensitivity, precision and accuracy of this method was suitable for the characterization of the pharmacokinetics and the CNS distribution of I, following administration of intravenous (i.v.) infusion, single i.v. bolus and multiple i.v. bolus doses of I to freely moving rats, with continuous microdialysate sampling of multiple tissues and simultaneous on-line HPLC analysis. Pharmacokinetic parameters for I, as determined from concentrations in blood MD samples with on-line analysis, were in good agreement with those estimated from concentrations in the UF of plasma samples obtained by conventional sampling.

Zidovudine transport in the rabbit brain during intravenous and intracerebroventricular infusion.

The distribution of zidovudine (AZT) between plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF) was investigated in a crossover design study (n = 5) in unanesthetized rabbits. Drug was administered by intravenous (iv) and intracerebroventricular (icv) infusions at the same infusion rate (1.5 mg/h.kg). The concentrations of AZT in ECF and CSF were measured by HPLC with microdialysis sampling. Plasma concentrations of AZT were quantitated by HPLC. Following iv infusion, the ECF- and CSF-to-plasma concentration ratios at steady state (SS), were 0.19 +/- 0.05 and 0.29 +/- 0.06, respectively. These values were less than unity, indicating the existence of active transport processes for the transport of AZT from brain to plasma across the blood-brain barrier (BBB) or blood-CSF barrier (BCB). The transport processes were modeled by compartmental model analysis, and the results suggest that the transport efficiency of AZT across the BBB is asymmetric; that is, the efflux clearance was five times greater than the influx clearance. Similarly, the efflux clearance from CSF is three times larger than the influx clearance into CSF. The SS concentrations of AZT in brain ECF in the same animals that received an icv infusion of AZT in the crossover design study were approximately two orders of magnitude greater than those in animals following iv infusion at the same dosing rate. Nevertheless, the SS plasma concentrations of AZT were similar for both routes of administration (1.2 +/- 0.19 and 1.2 +/- 0.13 micrograms/mL for iv and icv routes, respectively), confirming that the brain is not an organ that exhibits first-pass metabolism under the present experimental conditions.

Analysis of diclofenac and four of its metabolites in human urine by HPLC.

An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3'-hydroxydiclofenac, 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxy-4'-methoxydiclofenac) in human urine is described. Following base hydrolysis, the samples were neutralized and extracted. Evaporated extracts were reconstituted in mobile phase containing ascorbic acid, and chromatographed, using flow-rate programming, on a reversed-phase column. Absolute recovery (average), was at least 78% for diclofenac and ranged from 75 to 85% for the four metabolites. Standard curves showed linearity over the range of concentrations of 0.2 to 40 ug/mL, using 0.25 mL of urine. Specificity was demonstrated by examining chromatograms of extracts of blank urine from 8 volunteers and 24 study subjects. Good accuracy was observed for all compounds over the concentration range of 0.2 to 40 ug/mL using 0.25 mL of urine. Based on accuracy and precision criteria, the limit of quantitation for all 5 analytes was 0.4 ug/mL, using 0.25 mL of urine. Analysis of urine from subjects with normal and reduced renal function who received diclofenac orally demonstrated that total diclofenac and metabolites excreted in the urine represented approximately 31% and 4% of an oral dose of diclofenac, respectively.

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 (fu) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (Cu) and plasma (Cp), 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 Cu to Cp 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 Cu and Cp at any urine flow rate was reached and, therefore, the Cu to Cp ratio will not be equal to fu.

Transsynovial drug distribution: synovial mean transit time of diclofenac and other nonsteroidal antiinflammatory drugs.

The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid concentration-time data taken from the literature for four other nonsteroidal antiinflammatory drugs (etodolac, ibuprofen, indomethacin, and tenoxicam) were also analyzed. The two methods of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration-time curve to the area under the plasma concentration-time curve. Both methods can be considered noncompartmental because in determining the first-order exit rate constant for the synovial fluid (the inverse of the synovial mean transit time), an analysis of the overall distribution and elimination characteristics of the drug is unnecessary. Method 1 makes use of the information contained in the postdistributional synovial fluid to plasma concentration ratio whereas method 2 is a linear pharmacokinetic model using a partial-areas analysis. The single dose mean +/- S.D. synovial fluid exit rate constant for diclofenac was 0.39 +/- 0.33 hr-1 (n = 6), which was not significantly different from that determined by method 2; which was 0.49 +/- 0.52 hr-1. The steady state mean +/- S.D. diclofenac synovial fluid exit rate constants for methods 1 and 2 were 0.43 +/- 0.18 and 0.54 +/- 0.71 hr-1 (n = 8), respectively, which were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Thiamphenicol pharmacokinetics in beef and dairy cattle.

The pharmacokinetics of thiamphenicol were investigated in 10 calves and six lactating cows. It was found that this drug is rapidly absorbed (15 min) following intramuscular injection with an absorption rate constant and a bioavailability of 8.7 h-1 and 84%, respectively. The drug appears to be widely distributed into various body fluids, yielding a volume of distribution (Vd(area) of approximately 0.9 l/kg. The micro-rate constants indicated that the antibiotic rapidly diffuses into the peripheral compartment (k12 > k21). Elimination from plasma is relatively rapid, with a biological half-life of about 1.75 h. Thiamphenicol appears shortly in milk (15 min) after its intravenous administration, and gives milk to plasma concentration ratios greater than one between 4 and 12 h.

Investigation of the distribution of EAB 515 to cortical ECF and CSF in freely moving rats utilizing microdialysis.

A freely moving rat model was developed to study the CNS distribution of EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of the rat brain was performed to measure the levels of EAB 515 in the cortical extracellular fluid (ECF) as well as in the cerebrospinal fluid (CSF). The femoral artery and femoral vein were cannulated for serial blood sampling and intravenous (i.v.) drug administration, respectively. EAB 515 was also administered via the intracerebroventricular (icv) route in a cross-over experiment. The in vivo recovery of EAB 515 across the MD probes was determined by simultaneous retrodialysis (RD) performed using a hydroxylated analog of EAB 515, as the RD calibrator (RDC). An extremely sensitive and selective on-line HPLC system with native fluorescence detection was developed for the simultaneous analysis of EAB 515 and RDC in microdialysate samples from rat CSF and cortical ECF. Unbound concentrations of EAB 515 in the rat plasma were determined by direct injection of plasma ultrafiltrate onto the HPLC column. The validity of the use of RDC as the RD calibrator was demonstrated by comparing the results of zero-net flux (ZNF) analysis simultaneously in some experiments. After constant rate i.v. infusion in rats (n = 12) for 900 min, the average (S.D.) ratio of the levels of EAB 515 in the CSF to those in plasma (Ccsf.iv/Cp) was determined to be 17.7 (7.8)% and that in the cortex relative to plasma (Ccortex.iv/Cp) was 8.3 (4.8)%.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs.

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 +/- 17 vs 252 +/- 54 mL/hr/kg). The plasma levels of the metabolites 4'-hydroxy, 5-hydroxy, 3'-hydroxy, 4',5-dihydroxy, and 3'-hydroxy-4'-methoxy diclofenac were considerably lower in minipigs than in man after both i.v. and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (Ka = 0.52 +/- 0.11, 0.59 +/- 0.13, and 1.2 +/- 0.7 hr-1, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption.(ABSTRACT TRUNCATED AT 250 WORDS)