Toxicokinetics of ochratoxin A in several species and its plasma-binding properties

The toxicokinetic profile of ochratoxin A was studied after the oral or intravenous administration of 50 ng/g b.w. to fish, quail, mouse, rat and monkey. The elimination half-life varied from 0.68 h after oral administration to fish, up to 840 h after intravenous administration to monkey. The distribution volume ranged from 57 ml/kg in fish to 1500 ml/kg in quail. The plasma clearance was most rapid in quail and fish, 72 and 58 ml/kg.h, respectively, while it was only 0.17 ml/kg.h in monkey. The bioavailability was as low as 1.6% in fish but as high as 97% in mouse. The binding abilities of ochratoxin A to plasma proteins were also studied. From these data we calculated the free fraction of toxin in plasma, which we found to be less than 0.2% in all species investigated (including man) except fish. A similar but smaller investigation on the toxicokinetics and binding properties of ochratoxin B was also performed. Ochratoxin B was more readily eliminated and had a lower affinity for plasma proteins, which partly may explain its lower toxicity.     

Placental transfer of ochratoxin A and its cytotoxic effect on the mouse embryonic brain

Pregnant ICR mice were given a single ip injection of 5 mg ochratoxin A/kg on day 11 or 13 of pregnancy. Concentrations of ochratoxin A in the maternal serum and tissues reached maximum levels within 2 hr of the injection and then decreased rapidly. The half-life of the toxin in serum was 28.7 hr on day 11 and 23.6 hr on day 13. On the other hand, the concentrations of ochratoxin A in the embryos were very low 2 hr after injection and then gradually increased up to 48 and 30 hr after injection on day 11 and 13, respectively. Pharmacokinetically, the embryo was found to be a 'deep' compartment. In mice treated with ochratoxin A on day 10 of pregnancy, the incidence of pyknotic cells in the telencephalon of the embryos began to increase 12 hr after injection to a peak between 36 and 48 hr, coinciding with the time of peak concentration of the toxin in the embryo.     

Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans

The mycotoxin ochratoxin A (OTA) is a rodent carcinogen produced by species of the ubiquitous fungal genera Aspergillus and Penicillium. OTA is found in a variety of food items and as a consequence is also found in human plasma (average concentrations found in this study: 0.1-1 ng OTA/ml plasma). To improve the scientific basis for cancer risk assessment the toxicokinetic profile of OTA was studied in one human volunteer following ingestion of 395 ng 3H-labeled OTA (3.8 microCi). A two-compartment open model consisting of a central compartment was found to best describe the in vivo data. This two-compartment model consisted of a fast elimination and distribution phase (T1/2 about 20 h) followed by a slow elimination phase (renal clearance about 0.11 ml/min.) and a calculated plasma half-life of 35.55 days. This half-life was approximately eight times longer than that determined previously in rats. In addition, the intraindividual fluctuation of OTA plasma levels was investigated in eight individuals over a period of 2 months. The concentrations determined ranged between 0.2 and 0.9 ng OTA/ml plasma. The plasma levels in some individuals remained nearly constant over time, while others varied considerably (e.g. increase of 0.4 ng/ml within 3 days, decrease of 0.3 ng/ml within 5 days) during the observation period. This intraindividual fluctuation in OTA plasma levels, which may represent differences in OTA exposure and/or metabolism, as well as the large difference in plasma half-life in humans compared to rats must be taken into consideration when the results of rat cancer study data are extrapolated to humans for risk assessment purposes.     

Toxicokinetics of ochratoxin A in vervet monkeys (Cercopithecus aethiops)

The toxicokinetics of ochratoxin A were investigated in vervet monkeys (Cercopithecus aethiops). Three female monkeys were treated intravenously with ochratoxin A at doses, respectively, of 0.8, 1.5 and 2 mg/ kg body weight (BW). Blood and urine samples were collected over a period of 21 days. Plasma and urine extracts were analysed by high-performance liquid chromatography (HPLC) with either fluorescence or negative ion electrospray ionization mass spectrometric detection. The clearance of ochratoxin A from plasma followed a two-compartment model. The elimination half-life of ochratoxin A in the monkeys was determined to be 19-21 days and the average total body clearance was 0.22 +/- 0.07 ml/h per kg and the average apparent distribution volume of the central compartment was 59 +/- 9 ml/kg and the peripheral compartment was 59 +/- 20 ml/kg. No evidence was found for any metabolic conversion of ochratoxin A.     

Role of ochratoxin in disease causation.

Under experimental conditions renal damage has been induced by alimentary exposure to ochratoxin A in all single-stomach animals tested so far, including rodents, dogs, pigs and birds, and even in young ruminants still functioning as single-stomach animals. Most information on ochratoxin-induced nephropathy has been obtained in pigs during experimental studies comprising structural as well as functional changes. The renal damage is characterized morphologically by atrophy of the proximal tubules, interstitial cortical fibrosis and sclerotized glomeruli, and functionally by impairment of tubular function indicated by a decrease in TmPAH/Cin and reduced ability to produce concentrated urine. The renal effect has been observed using exposure levels of ochratoxin A in the range 200 to 4000 micrograms/kg feed. Field cases of ochratoxin-induced nephropathy in pigs have been encountered in many countries, and the disease mycotoxic porcine nephropathy (MPN) is recognized as an endemic disease entity in several northern and central European countries. Epidemics of MPN have been reported, closely related to excessive climatic conditions in periods preceding harvest. Ochratoxin A is a recognized renal carcinogen in the mouse. In female pigs exposed to alimentary ochratoxin A for 2 years, no renal cancer was observed. Ochratoxin A is metabolized and excreted relatively fast in animals, with an RL50 (residue elimination) in the pig of a few days for various tissues. Past exposure data is a requirement in retrospective epidemiological studies, but because of the short RL50 values tissue analysis for ochratoxin A is unlikely to provide that kind of data, in animals or in humans. In order to meet this demand a procedure has been developed, using renal biopsy material for activity analysis of two renal tubular enzymes, phosphoenolpyruvate carboxykinase and gamma-glutamyl transpeptidase. In pigs exposed to ochratoxin A for 1 week a 40% reduction of the enzyme activity was observed. The dose-related activity decrease of the two enzymes was accompanied by a dose-related aggravation of renal impairment, as measured by a reduction of TmPAH/Cin, suggesting that these enzymes are sensitive indicators of ochratoxin A-induced nephropathy.     

Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs.

Gemcitabine, 2'-deoxy-2',2'-difluorocytidine, is a broad spectrum oncolytic compound with antitumor activity in solid tumor models. The pharmacokinetics, metabolism, and disposition of gemcitabine was examined in mice, rats, and dogs. All three species metabolize gemcitabine by deamination to the uracil metabolite. However, deamination in the mouse and dog was more extensive than in the rat. The mouse deaminated gemcitabine rapidly with the plasma concentration maximum of the uracil metabolite of gemcitabine being attained at 15 min postdosing compared with approximately 3 and 6 hr in the dog and rat, respectively. The rapid deamination in the mouse was also reflected in the plasma half-life of the parent compound. The mouse exhibited the shortest plasma half-life, approximately 0.28 hr, contrasted with 2.14 and 1.38 hr half-lives in rat and dog, respectively. Plasma AUC for the uracil metabolite of gemcitabine was 73%, 10.5%, and 315% of that for gemcitabine in the mouse, rat, and dog, respectively. Tissue concentrations of gemcitabine-derived radioactivity in the rat and mouse indicated that gemcitabine was rapidly distributed throughout the body. Half-lives of radioactivity in tissues of both the rat and mouse were relatively short, with the longest tissue half-lives of 5.7 and 3.0 hr, respectively. Plasma protein binding is negligible in all three species. The major route of elimination is via the urine in all three species with 76-86% of the dose excreted in the first 24 hr. The predominant radiolabeled component isolated from urine was gemcitabine in the rat and its uracil metabolite in the mouse and dog.     

Clinical pharmacokinetics of carboplatin

The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high-performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein-bound platinum and metabolites, declined triexponentially; plasma half-lives (t1/2 lambda 1, 0.2 to 0.4 hr; t1/2 lambda 2, 1.3 to 1.7 hr; t1/2 lambda 3, 22 to 40 hr) and total body clearance (CLTB 2.8 +/- 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterable platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2 lambda 1, 0.50 hr; t1/2 lambda 2, 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (t1/2-26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half-life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first-generation analog cisplatin.     

Synergistic toxic effects of citrinin,ochratoxin A and penicillic acid in mice

G. A. Sansing, E. B. Lillehoj, R. W. Detroy and M. A. Miller. Synergistic toxic effects of citrinin, ochratoxin A and penicillic acid in mice. Toxicon14, 213–220, 1976.—The ld₅₀'s in mice of citrinin, ochratoxin A, and penicillic acid injected intraperitoneally were 89, 22, and 100 mg per kg of body weight, respectively. Paired combinations of the mycotoxins, citrinin: ochratoxin A (CI:OA), ochratoxin A:penicillic acid (OA:PA), and penicillic acid:citrinin (PA:CI) elicited synergistic lethal responses. After administration of citrinin, ¹⁴C-orotic acid incorporation into both liver and kidney increased significantly by 27 hr with a return to control levels at 51 hr. Treatment with penicillic acid also increased orotic acid incorporation into liver ribonucleic acid (RNA) at 27 hr and at 4 hr in the kidney. Ochratoxin A inhibited orotic acid incorporation into both liver and kidney RNA 6 hr after toxin injection with a subsequent return to control levels at 27 hr. Orotic acid incorporation was inhibited in both kidney and liver 6 hr after treatment with the toxin combination CI:OA, PA:CI stimulated precursor incorporation into kidney RNA at 27 hr and inhibited the function in liver. The OA:PA combination inhibited orotic acid incorporation in both organs 15–27 hr after toxin treatment.     

Binding of perfluorooctanoic acid to rat liver-form and kidney-form alpha2u-globulins

Perfluorooctanoic acid (PFOA) is an organic fluorochemical and is reported to have a long half-life in human blood. Its urinary elimination in rats is markedly sex-dependent, and characterized by significantly longer plasma half-life of PFOA in male rats than in females. It has been postulated that male-specific PFOA binding protein(s) is responsible for the long half-life of PFOA in male rats. In this paper, two male rat specific proteins, liver- and kidney-form alpha2u-globulins (A2U(L) and A2U(K)), were purified from male rat urine and kidney, respectively. The binding of these two nroteins to PFOA was investigated using ligand blotting, electrospray ionization mass spectrometry and fluorescence competitive binding assay. The results revealed that both A2U(L) and A2U(K) were able to bind PFOA in vitro under physiological conditions, and that PFOA and a fluorescent-labeled fatty acid shared the same binding site on both A2U(L) and A2U(K). The binding affinities, however, are relatively weak. The estimated dissociation constants are in the 10(-3) M range, indicating that bindings of PFOA to either A2U(L) or A2U(K) cannot adequately explain the sex-dependent elimination of PFOA in rats, and it is unlikely that PFOA-A2U(K) binding would induce A2U nephropathy as seen with, for example, 1,4-dichlorobenzene.     

Ochratoxin A in human blood in Abidjan, Côte d''Ivoire

Ochratoxin A (OTA) produced by Aspergillus and Penicillium genera contaminates a diversity of foods including cereals; cereals-derived foods; dry fruits; beans; cocoa; coffee; beer; wine; and foodstuffs of animal origin mainly poultry, eggs, pork and milk, including human breast milk. OTA is nephrotoxic to all animal species studied so far and most likely to humans, who show the longest half-life for elimination of this toxin among all species examined. Among other toxic effects, OTA is teratogenic, immunotoxic, genotoxic, mutagenic and carcinogenic, all of which lead to life-threatening pathologies through several molecular pathways.

In Côte d'Ivoire, preliminary surveys conducted by us have proven from 1998 to 2004 the reality of ochratoxin A-contamination of foodstuffs.

To assess OTA in human blood, the immunoaffinity columns were used along with HPLC for separation and fluorimetric quantification of blood samples collected in Abidjan from two categories of people: apparently healthy donors (n=63) and nephropathy patients undergoing dialysis (n=39).

Among healthy donors, 34.9% show OTA concentrations ranging from 0.01 – 5.81 μg/l with a mean value of 0.83 μg/l, whereas, among nephropathy patients undergoing dialysis 20.5% are OTA positive in a range of 0.167–2.42 μg/l and a mean value of 1.05. Although the sex ratio is 0.82 (46 females for 56 males) ochratoxin A contamination is equally distributed in both sexes. Nephropathy patients undergoing dialysis appear, however, less frequently contaminated than healthy donors (20.5 versus 34.9%) and show higher OTA concentrations (higher mean value, p=0.01). Ochratoxin A concentrations found in human blood reflect concentrations previously detected in cereals and peanuts according to the eating habits and diets of people in Côte d'Ivoire. But, the prevalence of ochratoxin A in blood of nephropathy people undergoing dialysis appears lower than expected from the frequency of OTA contamination in cereals and peanuts. Pearson χ²-test indicates that among OTA-positive individuals renal dialysis and age are important modalities for consideration.     

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to rats and dogs

Clearance of ¹⁴C activity from the plasma and its elimination from the body of rats and dogs were determined after single oral doses of [carboxy-¹⁴C]2,4,5-T. The half-life values for the clearance of ¹⁴C activity from the plasma of rats given doses of 5, 50, 100 or 200 mg/kg were 4.7, 4.2, 19.4 and 25.2 hr, respectively; half-lives for elimination from the body were 13.6, 13.1, 19.3 and 28.9 hr, respectively. The apparent volume of distribution also increased with dose. Urinary excretion of unchanged 2,4,5-T accounted for most of the ¹⁴C activity eliminated from the body of rats. A small amount of unidentified metabolite was detected in the urine when rats were given 100 or 200 mg/kg but not 5 or 50 mg/kg. These results show that the distribution, metabolism and excretion of 2,4,5-T are markedly altered when large doses are administered.In dogs given 5 mg/kg, the half-life values for clearance from plasma and elimination from the body were 77.0 and 86.6 hr, respectively, offering a plausible explanation of why 2,4,5-T is more toxic in dogs than in rats. Appreciable excretion in the feces was noted and three unidentified metabolites were detected in urine of dogs, indicating a considerable difference in metabolism of 2,4,5-T by dogs and rats given the same dose.     

Bioavailability, metabolism, and renal excretion of benzoic acid in the channel catfish (Ictalurus punctatus)

The pharmacokinetics and metabolism of the model compound benzoic acid were examined after intravascular (iv) and po administration at 10 mg/kg in the channel catfish (Ictalurus punctatus). A two-compartment pharmacokinetic model best described the plasma disposition of parent benzoic acid after iv dosing. The following pharmacokinetic values were estimated: elimination half-life, 5.9 hr; total body clearance, 61 ml/hr/kg; and volume of distribution (steady-state), 369 ml/kg. Plasma protein binding of [14C]benzoic acid was 18%. Benzoic acid was rapidly and extensively absorbed after po administration; absorption half-life was 0.8 hr and bioavailability was 95%. Renal excretion was the primary route of elimination of benzoic acid and metabolites. More than 80% of the iv-administered 14C was recovered in the urine in 24 hr. Unchanged benzoic acid comprised more than 90% of the urinary radiolabel. The major urinary metabolite was benzoyltaurine, which comprised 6-7% of the excreted 14C. Channel catfish were qualitatively similar to other teleost fishes in the formation of the taurine conjugate of benzoic acid. In contrast, the primary mammalian metabolite is the glycine conjugate, hippuric acid.     

Toxicokinetic study and absolute oral bioavailability of deoxynivalenol,T-2 toxin and zearalenone in broiler chickens

Mycotoxins lead to economic losses in animal production. A way to counteract mycotoxicosis is the use of detoxifiers. The European Food Safety Authority stated that the efficacy of detoxifiers should be investigated based on toxicokinetic studies. Little information is available on the absolute oral bioavailability and the toxicokinetic parameters of deoxynivalenol, T-2 and zearalenone in broilers. Toxins were administered intravenously and orally in a two-way cross-over design. For deoxynivalenol a bolus of 0.75 mg/kg BW was administered, for T-2 toxin 0.02 mg/kg BW and for zearalenone 0.3 mg/kg BW. Blood was collected at several time points. Plasma levels of the mycotoxins and their metabolite(s) were quantified using LC–MS/MS methods and toxicokinetic parameters were analyzed. Deoxynivalenol has a low absolute oral bioavailability (19.3%). For zearalenone and T-2 no plasma levels above the limit of quantification were observed after an oral bolus. Volumes of distribution were recorded, i.e. 4.99, 0.14 and 22.26 L/kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. Total body clearance was 0.12, 0.03 and 0.48 L/min kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. After IV administration, T-2 toxin had the shortest elimination half-life (3.9 min), followed by deoxynivalenol (27.9 min) and zearalenone (31.8 min).     

Integrating variability in half-lives and dietary intakes to predict mercury concentration in hair

Methylmercury (MeHg) is a bioaccumulative environmental toxin that exerts its effect on fetal and infant neurodevelopment. Mercury concentration in hair is a good biomarker of MeHg accumulation in the body, with seafood being the main source of MeHg in humans. Therefore, modeling the link between food intake and mercury concentration in hair is a key step in assessing the risk of MeHg exposure. Using repeated measurements of diet and mercury concentration in hair, we studied 125 French pregnant women who consumed seafood (e.g., fish, mollusks and crustaceans) and compared their individual estimated dietary MeHg intakes with their hair mercury concentrations. We used a one-compartment toxicokinetic model for these comparisons. We integrated and estimated the between-person variability in MeHg half-life into the model. In a second model, we took into account an intra-individual MeHg intake variability to improve the performance of the toxicokinetic model.     

Physiologically based toxicokinetic modeling of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss)

A physiologically based toxicokinetic model for fish was used to simulate the uptake and disposition of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss). Trout were exposed to 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane in fish respirometer-metabolism chambers to assess the kinetics of chemical accumulation in arterial blood and chemical extraction efficiency from inspired water. Chemical residues in tissues were measured at the end of each experiment. Trout exposed to tetrachloroethane were close to steady-state in 48 hr. Fish exposed to pentachloroethane were near steady-state in 264 hr. Extraction efficiency data showed that systemic (extrabranchial) elimination of both chemicals was small. Hexachloroethane continued to accumulate in fish exposed for 600 hr. Parameterized with chemical partitioning data obtained in vitro, the model accurately simulated the uptake of all three chloroethanes in blood and tissues and their extraction from inspired water. These results provide support for the basic model structure and the accuracy of physiological input parameters.     

Relevance of a rat model of papillary necrosis and upper urothelial carcinoma in understanding the role of ochratoxin A in Balkan endemic nephropathy and its associated carcinoma.

Ochratoxin A is nephrotoxic and has been implicated in the genesis of Balkan endemic nephropathy (BEN), a condition that leads to end-stage renal disease and upper urothelial tumours. This compound induces renal parenchymal carcinoma in male mice only, and is not considered to be a potent carcinogen nor is there experimental evidence of its propensity to cause upper urothelial carcinoma. There is, however, evidence that exposure to more than one mycotoxin may be an important factor in the clinical spectrum of BEN. Analgesic nephropathy is clinically different, but is also associated with an upper urothelial carcinoma. The combination of urothelial initiation and an acute papillary necrosis in rats produces upper urothelial carcinoma. This two-stage experimental model offers the potential to assess the role of ochratoxin A in BEN-associated upper urothelial carcinoma under experimental conditions.     

Comparative pharmacokinetics of coumarin anticoagulants. XIV: relationship between protein binding, distribution, and elimination kinetics of warfarin in rats.

The relationships between the protein binding, distribution in the body, and kinetics of elimination of warfarin were studied. Individual rats eliminated warfarin by apparent first-order kinetics, with a biological half-life of 5.9-41 hr and a total plasma clearance of 2.4-22 ml kg(-1) hr(-1). There is a strong positive correlation between the apparent volume of distribution (Vd) and the elimination rate constant (kel). There was no apparent concentration dependance of warfarin binding to serum proteins over a wide concentration range, but there were pronounced intersubject variations in protein binding, with the free fraction of drug (f) in serum ranging from 0.172 x 10(-2) to 1.53 x 10(-2). There are strong positive correlations between f and kel, f and Vd, and f and the kidney-serum concentration ratio of warfarin. Consistent with theory, there is an excellent positive linear correlation between f and total plasma clearance of the drug. The intersubject variation in f is not related to variations in serum albumin or total protein concentration. There is a strong correlation between values of f for serum and liver homogenate in individual animals, consistent with the lack of correlation between f in serum and the liver-serum concentration ratio of warfarin. These results show that the pronounced intersubject variation in the elimination of warfarin observed in this investigation was related to interindividual differences in plasma protein binding of the drug. The differences in protein binding cannot be ascribed to differences in plasma protein concentrations and may reflect configurational differences of proteins or the presence of an endogenous displacing agent at different concentrations.     

Physiologically based toxicokinetic modeling of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss)

A physiologically based toxicokinetic model for fish was used to simulate the uptake and disposition of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss). Trout were exposed to 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane in fish respirometer-metabolism chambers to assess the kinetics of chemical accumulation in arterial blood and chemical extraction efficiency from inspired water. Chemical residues in tissues were measured at the end of each experiment. Trout exposed to tetrachloroethane were close to steady-state in 48 hr. Fish exposed to pentachloroethane were near steady-state in 264 hr. Extraction efficiency data showed that systemic (extrabranchial) elimination of both chemicals was small. Hexachloroethane continued to accumulate in fish exposed for 600 hr. Parameterized with chemical partitioning data obtained in vitro, the model accurately simulated the uptake of all three chloroethanes in blood and tissues and their extraction from inspired water. These results provide support for the basic model structure and the accuracy of physiological input parameters.     

Effects of phenobarbital and 3-methylcholanthrene pretreatment on the plasma half-life and urinary excretion profile of theophylline and its metabolites in rats

The effects of the inducers of the hepatic microsomal enzyme system, phenobarbital and 3-methylcholanthrene, on theophylline plasma half-life and on the elimination of theophylline and its metabolites in urine and feces have been examined. The results indicate that induction of the hepatic microsomal drug-metabolizing enzyme system significantly decreases plasma theophylline half-life. In this respect, 3-methylcholanthrene was more effective than phenobarbital. Control theophylline half-life was 3.5 hr. After phenobarbital or 3-methylcholanthrene pretreatment, the theophylline half-life was 2.6 and 0.8 hr respectively. Thin-layer Chromatographie analysis of the urine showed three radioactive peaks corresponding to 1,3-dimethyluric acid, 1-methyluric acid and unchanged theophylline. Both inducing agents significantly increased the urinary elimination of 1,3-dimethyluric acid above that seen in control animals throughout the 24-hr collection period, but only 3-methylcholanthrene increased the total amounts of 1-methyluric acid excreted. Urinary elimination of unchanged theophylline was decreased from control values by both agents. A small, but not statistically significant, increase in the fecal elimination of radioactive material was also noted in the animals pretreated with phenobarbital. The results indicate that alteration in hepatic drug-metabolizing activity may markedly affect the in vivo biotransformation of theophylline.     

Single Dose Pharmacokinetics of Doxepin in Healthy Volunteers

Abstract: The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers. Doxepin (DOX) and desmethyldoxepin (DDOX) concentrations in serum (or plasma) and red blood cells (RBCs) were measured by radioimmunoassay. Peak serum concentrations of DOX were observed at 1–2 hours and they ranged between 59.1–107.4 nmol/1. DOX disappearance was biphasic with a mean distribution half-life of 2.0 hrs and elimination half-life of 17.9 hrs. The mean total apparent volume of distribution was 22.7 l/kg and plasma clearance 0.93 l/hr/kg. The estimated mean first-pass metabolism of DOX was 71 % assuming complete absorption. Peak DDOX concentrations were observed at 1–6 hours and they ranged between 35.0–117.8 nmol/1. DDOX elimination was monophasic with a mean apparent half-life of 28.5 hours. Equilibrium dialysis gave a mean protein binding of 75.5% for DOX and 76.0% for DDOX. A highly time dependent and interindividually variable RBC/plasma concentration ratio was observed for both substances. Initially the plasma concentrations were 3–4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma. The major reason for this seemed to be a slower elimination of both drugs from the erythrocytes than from plasma.