Studies on the in vivo metabolism of hydralazine in the rat

A single dose of [1-14C]hydralazine is extensively metabolized in the rat as no unchanged drug is excreted in the urine, the major route of elimination of the drug. However, only a small proportion of the dose could be accounted for as known metabolites. The lack of expired 14CO2 suggests that the phthalazine ring is metabolically stable. The metabolites were qualitatively but not quantitatively similar to those excreted by human subjects. The three major urinary metabolites were found to be 3-methyl-s-triazolo[3,4a] phthalazine and acid-labile conjugates of hydralazine and 1-hydrazinophthalazin-4-one. There were also small amounts of s-triazolo[3,4-a]-phthalazine, 3-hydroxymethyl-s-triazolo[3,4-a]-phthalazine, hydrazine, and phthalazin-1-one. Induction of the microsomal enzymes by pretreatment with 3-methylcholanthrene reduced the excretion of the acetylated metabolite 3-methyl-s-triazolo[3,4-a]phthalazine, of conjugates of hydralazine and 1-hydrazinophthalazin-4-one. Pretreatment with phenobarbital reduced excretion of 3-methyl-s-triazolo[3,4-a]phthalazine. Conversely, inhibition of the microsomal enzymes by pretreatment with piperonyl butoxide increased the excretion of 3-methyl-s-triazolo[3,4-a]phthalazine and decreased the excretion of 1-hydrazinophthalazin-4-one conjugates. [14C]Hydralazine or a metabolite was covalently bound to tissue protein, particularly in the aorta, lungs, and spleen. Induction of the microsomal enzymes with 3-methylcholanthrene reduced and inhibition of the microsomal enzymes increased the binding to the aorta. In conclusion, the covalent binding of [14C]hydralazine or a metabolite to protein does not appear to be mediated by the microsomal enzymes in the rat and the metabolism of hydralazine in the rat shows considerable quantitative differences from that in man.     

Pharmacokinetics and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage

Ethylene dichloride (EDC) induces tumors in rats and mice when administered chronically by gavage. However, chronic inhalation of EDC vapor failed to induce any treatment-related tumors. To help understand the consequences of environmental exposure to EDC by either route, [¹⁴C]EDC was administered to male Osborne-Mendel rats by gavage (150 mg/kg in corn oil) or inhalation (150 ppm, 6 hr). EDC was extensively metabolized following either exposure. No significant differences were observed in the route of excretion of nonvolatile metabolites. In each case, ～85% of the total metabolites appeared in the urine, with 7 to 8, 4, and 2% found in the CO₂, carcass, and feces, respectively. The major urinary metabolites were thiodiacetic acid and thiodiacetic acid sulfoxide, suggesting a role for glutathione in biotransformation of EDC. Gross macromolecular binding (primarily protein binding) was studied after inhalation or gavage. No marked differences were noted between the two routes, or between “target” and “nontarget” tissues, after in vivo administration of EDC. Covalent alkylation of DNA by EDC was studied in Salmonella typhimurium and rats. DNA alkylation in S. typhimurium was directly related to the frequency of mutation in these bacteria. However, when DNA was purified from the organs of rats exposed in vivo to EDC, very little alkylation was observed after either gavage or inhalation (2 to 20 alkylations per million nucleotides). DNA alkylation after gavage was two to five times higher than after inhalation, but no marked differences were noted between target and nontarget organs. Pharmacokinetic studies indicated that peak blood levels of EDC were approximately five times higher after gavage than after inhalation. When pharmacokinetic data were modeled, it appeared that the elimination of EDC may become saturated when high blood levels are produced and that such saturation is more likely to occur when equivalent doses are administered by gavage versus inhalation. Since toxicity often occurs when the normal detoxification pathways are overwhelmed, this toxicity may represent the most reasonable explanation for the apparent differences between the two bioassays.     

Effect of butylated hydroxytoluene on the disposition of [14C]aflatoxin B1 in the lactating rat

The distribution and metabolism of an ip dose of [14C]aflatoxin B1 (AFB1) were studied in lactating Sprague-Dawley rats fed for the previous 13 days on a diet containing 0.5% butylated hydroxytoluene (BHT). Compared with ingestion of a BHT-free diet, treatment with BHT increased the biotransmission of AFB1 metabolites, predominantly aflatoxin M1 (AFM1), into the mammary gland and its content of milk, decreased AFB1 binding to liver nuclear DNA and enhanced the excretion of water-soluble metabolites of AFB1, all measured 6 hr after an oral dose of [14C]AFB1. These changes are related to the induction by BHT of hepatic enzymes involved in the transformation and detoxification of AFB1. The results suggest that exposure to BHT may protect the lactating animal from the carcinogenic effect of AFB1 but may increase the risk of exposure of the newborn infant to the carcinogenic metabolite AFM1.     

Effect of thiocarbonyl compounds on alpha-naphthylisothiocyanate-induced hepatotoxicity and the urinary excretion of [35S]alpha-naphthylisothiocyanate in the rat

The effect of disulfiram (DSF), sodium diethyldithiocarbamate (DDTC), methyl diethyldithiocarbamate (Me-DDTC), and ethionamide on the hepatotoxic response of alpha-naphthylisothiocyanate (ANIT) was studied in the rat. The hyperbilirubinemic response of ANIT was significantly inhibited by ip or po DSF pretreatment. A more marked inhibition of toxicity occurred when DSF was given via ip injection. DDTC, Me-DDTC, and ethionamide significantly inhibited ANIT-induced hyperbilirubinemia. Me-DDTC is approximately three times more potent than DDTC as an inhibitor of toxicity. Approximately 16% of a dose of [35S]ANIT was excreted in the urine as inorganic sulfate 48 hr after dosing. Me-DDTC administered simultaneously with [35S]ANIT significantly reduced urinary [35S]sulfate excretion in the first 24 hr. Ethionamide reduced urinary [35S]sulfate excretion. Pretreatment with phenobarbital which stimulates toxicity in vivo increased urinary [35S]sulfate excretion 300% in the first 12 hr. Thus, this study shows that agents which sensitize or protect rats from the toxic effects of ANIT, correspondingly stimulate or inhibit the oxidative desulfuration of [35S]ANIT in vivo.     

Effect of butylated hydroxytoluene pretreatment on the excretion, tissue distribution and DNA binding of [14C]aflatoxin B1 in the rat

The effect of butylated hydroxytoluene (BHT) pretreatment (0.5% in the diet for 10 days) on the excretion, tissue distribution and DNA binding of orally administered [14C]aflatoxin B1 (AFB1) was determined in male Fischer F344 rats. The amount of radioactivity excreted in the urine and faeces by 24 hr was higher in BHT-treated rats than in controls. Treatment with BHT enhanced the excretion of water-soluble metabolites in the urine and in the large intestines plus faeces at the earlier sampling times. The amount of radioactivity bound to hepatic nuclear DNA was six times less in the BHT-pretreated rats than in controls 6 hr after administration of the isotope. The half-lives of [14C]DNA in the rat liver were 30 and 46 hr for control and BHT-pretreated rats, respectively. These results indicate that BHT pretreatment may protect the animal from the carcinogenic effects of AFB1 by enhancing the detoxification and excretion of the mycotoxin.     

Effect of sodium salicylate on the fate of warfarin in the rat

Salicylate (88.9 mg/kg, po) decreased the blood level of radioactivity emanating from [¹⁴C]warfarin (1 mg/kg, iv and po) during the 24 hr following drug administration, reduced the area under the blood radioactivity vs time curve, and shortened the half-life for elimination of radioactivity from the blood. During the first 6 hr after drug administration, salicylate increased the biliary excretion of radioactivity, which resulted in enhanced fecal excretion of warfarin and its metabolites. Salicylate administration initially increased and later decreased the amount of radioactivity in the liver, and increased the proportion of warfarin metabolites to unchanged warfarin in this organ. It did not affect the proportion of unchanged warfarin to metabolites in the blood, bile and urine, or the total amount of radioactivity excreted during 48 hr in the urine and feces. In vitro, salicylate decreased the binding of [¹⁴C]warfarin to rat serum proteins in a linear manner. It is concluded that, in the rat, salicylate competes with warfarin for serum protein binding sites, thereby facilitating its uptake by the liver. Second, through a combination of its choleretic action and effect on membrane transport, salicylate enhances the biliary excretion of warfarin and its metabolites, thus accounting for the decreased concentration in the blood and lowered antiboagulant action.     

Deposition, metabolism, and excretion of 1-[14C]nitropyrene and 1-[14C]nitropyrene coated on diesel exhaust particles as influenced by exposure concentration

Nitrated polycyclic aromatic hydrocarbons (nitro-PAH) have been detected in the environment, originating from sources such as diesel exhaust emissions and coal combustion fly ash. 1-Nitropyrene (NP) is a predominant mutagenic and carcinogenic nitro-PAH found in diesel exhaust emissions. Since inhalation of NP is a likely route of exposure in humans, it is important to determine the biological fate of inhaled NP both in its pure form and associated with particles. The purpose of this study was to determine the disposition of NP aerosols inhaled by rats. The studies described in this paper were designed to determine the deposition of [14C]NP over a range of exposure concentrations, identify the pathways and half-times for excretion of absorbed NP, and determine the distribution of inhaled NP and metabolites in tissues. Male F344 rats were exposed nose only to various concentrations of NP and NP coated on diesel exhaust particles (50-1100 ng/liter). The results indicate that, over the range of concentrations tested, pathways for excretion of [14C]NP equivalents in urine and feces were independent of the exposure concentration of NP, whether in its pure form or associated with diesel exhaust particles. In all cases, fecal excretion was the major route of elimination of [14C]NP equivalents, with about 2 times more excreted by this route than by urine. The fractional deposition of [14C]NP in the respiratory tract did not appear to be dependent on exposure concentration. Half-times for elimination of 14C in urine and feces were about 15 to 20 hr. In all exposures, 14C was widely distributed in the tissues examined. Analysis of the tissues for NP and its metabolites indicated that within 1 hr after exposure, greater than 90% of the 14C was NP metabolites. Lungs of rats exposed to [14C]NP coated on diesel exhaust particles contained nearly 5 times more 14C than lungs from rats exposed to pure aerosols of [14C]NP (148 vs 29 pmol/g lung) within 1 hr after exposure. This difference was increased to 80-fold at 94 hr after exposure (80 vs 1 pmol/g lung). Long-term clearance half-times of 14C from various tissues were similar. The results demonstrate that particle association of NP significantly alters the biological fate of inhaled NP.     

The fate of inhaled octane and the nephrotoxicant, isooctane, in rats

To determine if inhaled nephrotoxic branched and nonnephrotoxic straight chain alkanes differ substantially in their biological fate, male F344 rats were exposed to 14C-labeled isooctane and octane vapors at approximately 1 and 350 ppm by the nose-only mode for 2 hr. Radioactivity in exhalant, urine, and feces was determined for 70 hr post exposure, after which residual radioactivity in the rat carcasses was determined. Absorbed [14C]isooctane equivalents were eliminated almost exclusively via the kidneys, while absorbed [14C]octane equivalents were excreted about equally via the kidneys and as 14CO2. Kidney excretion of isooctane-introduced 14C was protracted over the entire 70 hr postexposure observation period whereas for octane-introduced 14C, kidney excretion was essentially complete after 10-20 hr. About 5% of the [14C]octane equivalents inhaled at 1 ppm remained in the carcass 70 hr after inhalation exposure. Two percent of the [14C]octane equivalents inhaled at 350 ppm and 1-2% of the [14C]isooctane equivalents inhaled at either 1 or 350 ppm remained in the carcass 70 hr after inhalation exposure. The different patterns of excretion of metabolites of isooctane compared to octane may be a factor affecting the differences in nephrotoxicity between these two compounds.     

The distribution and excretion of manganese: The effects of manganese dose, l-dopa,and pretreatment with zinc

The biliary excretion and tissue distribution of radiomanganese (⁵⁴Mn) was studied in rats, and the effects of varying the dose of Mn, coadministration of Mn with l-DOPA, and pretreatment with zinc (Zn) were determined. As the iv dose of Mn increased, the percentage of the administered dose (% AD) recovered in bile increased, that in liver decreased slingtly, and that in other tissues remained relatively constant. Synthesis of hepatic metallothionein by 24 hr pretreatment with Zn (10 mg/kg) affected neither the normal biliary excretion of ⁵⁴Mn nor the binding profile of ⁵⁴Mn in the liver cytosol. l-DOPA significantly depressed the biliary excretion of Mn without causing a significant change in the M % AD recovered from liver or other internal organs indicating a possible increase in the Mn content of peripheral tissues such as skeletal muscle and skin. The influence of Mn on the excretion of l-[³H]DOPA and its metabolites was minimal. Evidence was not found to support the hypothesis that the chelation of Mn by l-DOPA is an important in vivo mechanism influencing the distribution and excretion of either Mn or L-DOPA.     

Fate of hexachlorobenzene in C57BL/10 mice with iron overload

The distribution of radioactivity in male C57BL/10 mice dosed with [14C]hexachlorobenzene (HCB) was followed over 21 days and found to be high in adipose tissue and adrenals, moderate in thymus whereas liver was relatively poorly labelled. A predose of iron (500 mg/kg), which greatly promotes the porphyrogenic action of HCB in this strain, had only a small effect on the distribution of radioactivity in tissues and excreta. Iron induced excretion of urinary metabolites from HCB by C57BL/10 mice but not by the insensitive DBA/2 strain. However, there was no such difference in faecal metabolites, total metabolism was only slightly increased and there was no correlation between liver porphyrin levels and urinary excretion of metabolites by individual mice. At the end of 4 weeks exposure of iron-treated C57BL/10 mice to HCB urinary metabolites fell while porphyrin excretion continued to rise. Thus the considerable sensitisation of the C57BL/10 strain after iron overload to the induction of porphyria by HCB cannot be ascribed simply to enhancement of total metabolism but must be caused either by the formation of a specific undetected metabolite or induction of some other toxic process.     

Studies on the tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea in mice.

The tissue-disposition and fate of N-[14C]ethyl-N-nitrosourea has been studied in mice. A large part of the injected N-[14C]ethyl-N-nitrosourea radioactivity was found to be exhaled as 14CO2. Whole-body autoradiography showed evenly distributed radioactivity in most tissues shortly after the administration of N-[14C]ethyl-N-nitrosourea which probably is due to the homogeneously distributed substance and the non-enzymatically formed ethyl-carbonium ions which have reacted with the tissues. The blood-brain barrier seemed to have a capacity to partially prevent the uptake of the substance in the central nervous system. A high radioactivity was observed in the liver, which may imply that N-[14C]ethyl-N-nitrosourea is enzymatically decomposed in this tissue. An observed labelling of kidneys may be connected with urinary excretion of radioactivity. The radioactivity in the liver and kidney decreased at later survival intervals and a distribution pattern appeared, which was characterized by a labelling of tissues with a high protein or steroid synthesis and of fat containing tissues. The distribution pattern corresponded to the one seen after the administration of [14C]acetaldehyde and is probably due to normal biosynthetic incorporation of radioactivity in the 2-carbon pool. Pretreatments with pyrazole, nialamide and diethyldithiocarbamate caused a marked inhibition of the exhalation of 14CO2 and of the incorporation of radioactivity in the liver. This effect may be directed towards the decomposition of N-[14C]ethyl-N-nitrosourea itself, but an effect on the metabolism of formed 2-carbon fragments is also possible. The incorporation of radioactivity in other tissues was not influenced by the pretreatments.     

Macromolecular interactions of inhaled methylene chloride in rats and mice

The in vivo interaction of methylene chloride and its metabolites with F344 rat and B6C3F1 mouse lung and liver DNA was measured after inhalation exposure to 4000 ppm [14C]methylene chloride for 3 hr. DNA was isolated from the tissues 6, 12, and 24 hr after the start of exposure and analyzed for total radioactivity and the distribution of radioactivity within enzymatically hydrolyzed DNA samples. Covalent binding to hepatic protein was also measured. A further group of rats and mice were dosed intravenously with [14C]formate after exposure to nonradiolabeled methylene chloride for 3 hr to determine the pattern of labeling resulting from incorporation of formate into DNA via the C-1 pool. Low levels of radioactivity were found in DNA from lungs and livers of both rats and mice exposed to [14C]methylene chloride. Two- to fourfold higher levels were found in mouse DNA and protein than in rat. Chromatographic analysis of the DNA nucleosides showed the radioactivity to be associated with the normal constituents of DNA. No peaks of radioactivity were found that did not coincide with peaks of radioactivity present in hydrolyzed DNA from formate-treated rats and mice. Under the conditions of this study there was no evidence for alkylation of DNA by methylene chloride in either rats or mice.     

Metabolism and Disposition of the HIV-1 Protease Inhibitor Lopinavir (ABT-378) Given in Combination with Ritonavir in Rats, Dogs, and Humans

PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.     

Effect of aryl hydrocarbon hydroxylase induction on the in vivo covalent binding of 1-nitropyrene, benzo[a]pyrene, 2-aminoanthracene, and phenanthridone to mouse lung deoxyribonucleic acid

The effect of aryl hydrocarbon hydroxylase induction on the covalent binding of 1-nitropyrene (1-NP), benzo[a]pyrene (BaP), 2-aminoanthracene (2-AA), and phenanthridone (PNDO) to mouse lung DNA was investigated. Cytochrome P-450-dependent monooxygenases were induced in mouse lung by intratracheal instillation of BaP, Aroclor-1254, or coal gas condensate (CGC) 24 hr before instillation of [3H]BaP, [3H]-2-AA, [14C]-1-NP, or [14C]PNDO. All inducing agents increased the amount of radioactivity of [3H]BaP, [3H]-2-AA, and [14C]-1-NP or metabolites bound to DNA. However, pretreatment with BaP resulted in the highest amounts of radiolabels covalently bound to DNA. At 4 hr after instillation of radiolabels in BaP-induced mice, the amounts of [3H]BaP, [3H]-2-AA, and [14C]-1-NP bound to DNA were increased 5.4-, 5.2-, and 160-fold above that of control levels; the amount of 1-NP bound to DNA was fifty times higher than the amount bound by BaP. Labeled compounds were still bound to DNA 1 week after administration. [14C]PNDO was not bound to DNA in uninduced or induced mice. Based on the amount of labeled compounds bound to DNA, pretreatment of mice with BaP and CGC induced enzymes with similar specificities; however, enzymes induced by Aroclor were less effective in the metabolism of labeled compounds to DNA-bound products. These data show that specific cytochrome P-450-dependent monooxygenases are inducible in mouse lung and suggest that pre-exposure to inducing agents may be important in the potential toxicity to proximal tissues in direct contact with inhaled xenobiotics.     

Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys

DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.     

The distribution of [14C]dimethylnitrosamine in mice. Autoradiographic studies in mice with inhibited and noninhibited dimethylnitrosamine metabolism and a comparison with the distribution of [14C]formaldehyde

The distribution of [¹⁴C]dimethylnitrosamine was studied by wholebody autoradiography in mice. By applying low temperature autoradiography and autoradiography with dried tape sections in mice with inhibited (by pretreatment with pyrazole, ethanol, or nialamide) and noninhibited dimethylnitrosamine metabolism, a distinction was possible between the distribution of the volatile nonmetabolized dimethylnitrosamine and the nonvolatile metabolites. The results indicated a uniform distribution of the nonmetabolized dimethylnitrosamine in the body. At the short survival intervals, metabolites were trapped primarily in the liver and also to a low degree in the kidneys, probably reflecting the alkylating reactions and other reactions connected with the breakdown of dimethylnitrosamine. At the long survival intervals, metabolites also occurred in tissues with a rapid cell turnover and a high rate of protein synthesis. Since autoradiography of [¹⁴C]formaldehyde gave this distribution picture, incorporation of radioactivity from [¹⁴C]dimethylnitrosamine via [¹⁴C]formaldehyde in the one-carbon pool probably explains the labeling of these tissues. Pyrazole, ethanol, and nialamide strongly depressed the incorporation of radioactivity from [¹⁴C]dimethylnitrosamine into the acid-insoluble material of the liver. In addition, the pretreatments caused a strong inhibition of the exhalation of ¹⁴CO₂ from [¹⁴C]dimethylnitrosamine.     

The metabolism and disposition of fenofibrate in rat, guinea pig, and dog

The metabolism and disposition of orally administered single doses of [14C]fenofibrate (isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionate) have been studied in rat, guinea pig, and dog. In rats, the urinary excretion of 14C in 5 days varied from 11 to 51% of the dose and was markedly dependent upon the dose form given. The interpretation of these data in terms of factors affecting the absorption of fenofibrate from the gut is complicated by the enterohepatic recirculation of metabolites. The tissue distribution of 14C after oral administration of an ethanolic solution of fenofibrate has been studied in the rat. The only tissues in which the concentration of 14C exceeded that in the blood were the organs of absorption and elimination, the gut, liver, and kidneys. Guinea pigs excreted 53% of the dose in the urine in 5 days, with a further 34% in the feces, while in dogs the corresponding figures were 9% and 81%, respectively. In all three species, all the urinary metabolites were products of ester hydrolysis, and the principal excretion product was "reduced fenofibric acid" which arose by subsequent carbonyl reduction. Glucuronidation of fenofibric acid and "reduced fenofibric acid" was a very minor reaction in the rat and guinea pig and was not detected in the dog. In addition, polar unknown metabolite(s) were detected in all three species, but were not investigated further. The results are discussed in terms of the comparative disposition of fenofibrate and other hypolipidemic agents and the contribution of these findings to the safety assessment of such drugs.     

Chlordecone altered hepatic disposition of [14C]cholesterol and plasma cholesterol distribution but not SR-BI or ABCG8 proteins in livers of C57BL/6 mice

Organochlorine (OC) insecticides continue to occur in tissues of humans and wildlife throughout the world although they were banned in the United States a few decades ago. Low doses of the OC insecticide chlordecone (CD) alter hepatic disposition of lipophilic xenobiotics and perturb lipid homeostasis in rainbow trout, mice and rats. CD pretreatment altered tissue and hepatic subcellular distribution of exogenous [(14)C]cholesterol (CH) equivalents 4 and 16 h after a bolus intraperitoneal (ip) injection of 5 ml corn oil/kg that contained 10 mg CH/kg. CD pretreatment altered tissue distribution of exogenously administered [(14)C]CH by decreased hepatic and renal accumulation, and increased biliary excretion up to 300%. Biliary excretion of polar [(14)C]CH metabolites was not altered by CD. CD pretreatment decreased subcellular distribution of [(14)C]CH equivalents in hepatic cytosol and microsomes and lipoprotein-rich fraction-to-homogenate ratio. CD pretreatment increased the ratio of [(14)C]CH equivalents in high density lipoprotein (HDL) to that in plasma and reduced [(14)C]CH equivalents in the non-HDL fraction 4 h after a bolus lipid dose. CD pretreatment increased plasma non-HDL total CH by 80% 4 h after a bolus lipid dose. Scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G8 (ABCG8) proteins were quantified by western blotting in hepatic membranes from control and CD treated mice. Liver membrane contents of SR-BI and ABCG8 proteins were unchanged by CD pretreatment. The data demonstrated that a single dose of CD altered CH homeostasis and lipoprotein metabolism.     

Biliary and urinary excretion of drug conjugates: effect of diuresis and choleresis on excretion of harmol sulphate and harmol glucuronide in the rat.

1. Harmol (7-hydroxy-1-methyl-9H-pyrido [3,4b] indole) is converted to harmol sulphate and harmol glucuronide in the rat in vivo. Harmol sulphate is excreted mainly in urine, while harmol glucuronide is excreted about equally in bile and urine, when harmol is given intravenously. 2. In rats with ligated kidneys, only choleresis produced by glycodehydrocholate and dehydrocholate caused enhanced biliary excretion of harmol sulphate; harmol glucuronide was unaffected. Several other bile salts had no effect. 3. Mannitol diuresis markedly increased urinary excretion of harmol sulphate, and decreased its biliary excretion. Harmol glucuronide was much less affected. 4. Nafenopin pretreatment increased liver weight and bile flow, and enhanced biliary excretion of harmol sulphate at the expense of its urinary excretion. 5. For harmol sulphate, urine and bile are compensatory pathways of elimination that can be influenced by urine and bile flow changes through diuresis and choleresis.     

Imipramine-mediated effects on levodopa metabolism in man

The effect of imipramine (IMP) on levodopa (l-dopa) metabolism was studied in four normal subjects. IMP pretreatment for 3 consecutive days prior to the administration of 500 mg l-dopa moderately decreased the urinary excretion of dopa. Similarly, IMP pretreatment decreased the urinary excretion of dopamine, norepinephrine and their major acid metabolites. In contrast, IMP pretreatment decreased the urinary excretion of serotonin but increased the excretion of its major acid metabolite, 5-hydroxyindoleacetic acid. The findings suggest that IMP-mediated decreased excretion of dopa and its metabolites studied is partially related to retarded gastrointestinal absorption of l-dopa and that IMP may alter the metabolic pathway of serotonin during l-dopa administration in man.