Pharmacokinetic aspects of sulfobromophthalein transport after diethyl maleate pretreatment in rats

The pharmacokinetics of sulfobromophthalein was studied in the rat after depletion of hepatic glutathione levels induced by intraperitoneal administration of diethyl maleate (4.0 mmol/kg). After an intravenous bolus injection of sulphobromophthalein (120 mumol/kg) a biexponential plasma decay was found both in control and diethyl maleate pretreated rats. The initial plasma clearance Cl12 was not modified by diethyl maleate administration. The rate constant of biliary excretion K23 was significantly lowered in diethyl maleate pretreated rats, which could by explained by the change in the biliary excretory process. The cumulative biliary excretion of sulphobromophthalein was decreased by about 50% following diethyl maleate injection, with a reduction of the percentage of conjugated dye excreted into bile.     

Hepatic transport of indocyanine green in rats chronically intoxicated with carbon tetrachloride

Hepatic transport of indocyanine green (ICG) and probable factors altering the disposition of ICG were examined in rats chronically intoxicated with carbon tetrachloride. Delays were shown in both plasma disappearance and biliary excretion of ICG in intoxicated rats. No significant difference was shown in the total amount of ICG bound to the plasma proteins. In the intoxicated rats, significant decreases were observed in the pharmacokinetic parameters, k₁₂, k₃₄ and V₂, calculated by a three-compartment model, while a significant increase was observed in k₂₁; V₁ was not altered. In both the control and intoxicated rats, the values of k₁₂·V₁ were significantly smaller than the hepatic plasma flow, and it was suggested that the plasma flow does not play a primary role in the hepatic uptake of ICG. No significant difference was observed in the elution profiles of the 100,000 g supernatant fraction on a Sephadex G-75 column, and ICG bound mainly to the X-fraction in both the control and intoxicated rats. About 90 per cent of the ICG administered intravenously was distributed to the 9000g precipitate fraction by 5 min in both groups of rats. It was concluded that a decrease in the permeability of the sinusoidal plasma membrane of the hepatocyte may explain the decrease of ICG uptake rate by the livers of the intoxicated rats.     

Hepatic transport and biliary excretion of sulfobromophthalein in aflatoxin B1-treated rats

The effects of a single dose of aflatoxin B1 (AFB1) on sulfobromophthalein (BSP) plasma disappearance, hepatic transport maximum (Tm), and relative storage capacity (S), were examined in rats 48 hr after AFB1 injection. BSP plasma concentration decay was delayed, and the BSP biliary excretion was diminished in treated animals. S and Tm values were unaltered. However, the Tm was reached in treated rats at a higher infusion rate. A Lineweaver-Burk plot of BSP biliary excretion rate vs BSP serum concentration curve showed a higher apparent Km in the AFB1-treated rats.     

Pharmacokinetic modelling of blood-brain barrier transport of escitalopram in rats

This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood-brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 microl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents.     

Changes in auditory brainstem response in rats chronically exposed to carbon disulfide

The chronic effect of carbon disulfide (CS₂) on the central nervous system (CNS) was studied by examining auditory brainstem responses (ABRs) in female rats (Jcl Wistar) exposed to 200 ppm or 800 ppm CS₂ by inhalation, 6 h a day, 5 days a week, for 15 weeks. Two modes of ABRs evoked by clicks at 61 and 96 dB sound pressure levels (61 dB-ABR and 96 dB-ABR) were recorded during the exposure and for 6 weeks afterwards. Three main components (I, III and V) of ABRs were analyzed from the latencies and differences between latencies of them (interpeak latencies, IPL I–III, IPL III–V and IPL I–V). The latencies of the three components and IPLs of 96 dB-ABR in rats group exposed to 800 ppm of CS₂ were significantly delayed during the exposure period. The delay of latency of component V and IPL III–V and I–V tended to increase with exposure time. At 61 dB-ABR, the changes in the latency of component V, IPL III–V and I–V resembled those at 96 dB-ABR. For the rats group exposed to 200 ppm CS₂, the latency of component I, IPL III–V and I–V at 96 dB-ABR were delayed significantly but transiently during the exposure period. For both groups, recovery from the latencies of the three components and IPLs of ABR was observed by the end of the recovery period. The delayed latencies of ABR observed in rats exposed to 800 ppm CS₂ suggested a conduction dysfunction in the brainstem due to CS₂ exposure. The transient delay of the parameters in the rats group exposed to 200 ppm CS₂ was considered to represent a slight conduction dysfunction.     

Pharmacokinetic behavior of micafungin in rats with carbon tetrachloride-induced acute hepatic failure

We examined the pharmacokinetic behavior of micafungin, a novel antifungal agent, in rats receiving carbon tetrachloride (CCl4) at a single dose of 2.5 ml/kg. There was no significant change in the total clearance (CL(tot)) in CCl4-treated rats, while the steady-state volume of distribution (Vd(ss)) was significantly increased by CCl4 treatment. Alteration in the serum unbound fraction of micafungin after CCl4 treatment was unlikely in light of the serum albumin, bilirubin, creatinine, and urea nitrogen. The increased Vd(ss) was attributable to augmentation in the accessibility of micafungin to peripheral tissue without impairment of the intrinsic clearance, because slight enhancement of the tissue distribution of micafungin was confirmed following CCl4 treatment.     

Compartmental analysis of the effect of carbon tetrachloride intoxication on blood and bile kinetics of sulfobromophthalein in rats

In rats intoxicated by CCl₄ (2.5 ml/kg by stomach tube or 10 ml/kg i.m.), the plasma and bile BSP kinetics were fitted to a four-compartment model. The effect of CCl₄ was analyzed by the changes brought about in the five transfer constants which characterize the model. Intrahepatic BSP transfer and liver uptake are the parameters most sensitive to CCl₄ intoxication. The peak effect is obtained 1 day after the intoxication, with a rapid return to normality.Part of the present work has been performed under a grant from the Consiglio Nazionale delle Ricerche (Grant No. 71.0024.09).     

Pharmacokinetic aspects of biotechnology products

In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays--along with a newer generation of mass spectrometry-based techniques--can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes--a critical determinant for the drug's systemic exposure--may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future.     

Pharmacokinetic aspects of deprenyl effects

Deprenyl is a selective, irreversible inhibitor of monoamine oxidase type-B (MAO-B). In prolonged treatment (0.05-0.25 mg/kg, sc daily) in spite of the irreversible blocking, selective inhibition pattern of MAO was maintained. 14C-Deprenyl is well absorbed after oral or subcutaneous administration and penetrates rapidly to the central nervous system. When it is given intravenously its highest brain concentration is reached within 30 sec but radioactivity rapidly disappears from the central nervous system. Deprenyl is metabolized to amphetamine and methylamphetamine in rats without producing a remarkable sign of psychostimulant activity. This could partly be due to the distribution properties of deprenyl e.g. low detectable level of radioactivity in the brain after 1-2 min and partly to the fact that from (-) -deprenyl (-) -amphetamines, which have less psychostimulant activity than the (+) -isomere, are formed.     

Reduced bile flow in rats during sulfobromophthalein infusion.

Male urethane-anesthetized Wistar rats with biliary fistulas were infused intravenously with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) (594 nmol/100 g/min) for 100 min. With BSP infusion the bile flow increased for 25 min and subsequently fell almost linearly. Biliary excretion of BSP-GSH correlated with the bile flow, whereas the hepatic concentration of this metabolite rose during infusion. The concentration of unconjugated BSP also increased in the liver. On the other hand, the infusion of BSP-GSH resulted in a long lasting choleresis accompanied by high biliary concentrations of BSP-GSH without a concurrent increase in the concentration of BSP-GSH in the liver. It is concluded that the increasing concentration of unconjugated BSP in the liver leads to an impaired excretion of BSP-GSH in the bile and concurrently to a reduction in bile flow. The conjugation with glutathione may be the rate-limiting step in the biliary excretion of BSP.     

Enzymatic studies on tryptophan metabolism disorder in rats chronically exposed to carbon disulfide

Eight-week-old female Wistar rats were exposed to carbon disulfide for 6 hr a day, 5 days a week, for 12 weeks in inhalation chambers. Then the activities of the main enzymes of tryptophan metabolism (i.e., L-tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase, kynurenine 3-hydroxylase, kynureninase, and kynurenine aminotransferases) in their tissues were determined. The results showed that exposure to carbon disulfide caused a significant increase in the activities of kynureninase and kynurenine-2-oxoglutarate aminotransferase in the kidneys, but only a slight increase in their activities in the liver. The activities of L-tryptophan 2,3-dioxygenase and kynurenine 3-hydroxylase also tended to increase, but the increases were not statistically significant. These results suggests that the kynurenine pathway of tryptophan metabolism in the kidneys of rats exposed to carbon disulfide is activated and that the increased activities of kynurenine-2-oxoglutarate aminotransferase in the kidneys may cause the increased excretion of tryptophan metabolites after tryptophan loading as shown in an earlier study (A. Okayama, L. Fun, A. Yamatodani, Y. Ogawa, H. Wada, and S. Goto, 1987, Arch. Toxicol. 60, 460-463.     

Pharmacokinetic aspects of protriptyline plasma levels

Summary Plasma levels of protriptyline have been determined in 30 depressed female patients undergoing antidepressant therapy. After 3 1/2 weeks treatment at dosage levels of 40 mg/day, protriptyline plasma levels ranged from 430 to 1430 nmol/l. During this period only two-thirds of the subjects had definitely achieved asymptotic concentrations. Single dose studies in 5 volunteers suggest that the volume of distribution of protriptyline shows little intersubject variation. The half life of the drug, however, may vary appreciably from subject to subject, ranging from 54 to 198 h. The effects of two sedatives on mean protriptyline plasma levels have been determined. Mean plasma levels for nitrazepam recipients are indistinguishable from those for patients receiving no night sedation. The mean plasma levels for a group of patients receiving sodium amylobarbitone were significantly reduced. The problem of choice and early adjustment of dosages in order to achieve satisfactory plasma levels is discussed. For practical purposes it is suggested that early values may be of predictive significance in allowing early dosage adjustments to be made.     

Excretion of sulfobromophthalein in rats with iodomethane-induced depletion of hepatic glutathione

Summary Male urethane-anesthetized Wistar rats with biliary fistulas were infused for 60 min i.v. with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) at 594 nmol/100 g/min. Thirty minutes prior to the start of the infusion, 20 mg/kg iodomethane, dissolved in olive oil, was given into the duodenum. The control received oil only. At the start of the infusion the hepatic concentration of GSH was 0.96±0.23 mg/g liver in the iodomethanetreated animals versus 1.93±0.13 mg/g liver in the control (P<0.001).When unconjugated BSP was infused, the excretion of total BSP (unconjugated plus conjugated) was markedly lower in the iodomethane-treated group than in the control. This difference was due solely to differences in biliary appearing conjugated BSP; the excretion of unconjugated BSP was identical in both groups. The different excretion patterns were paralleled by equal hepatic accumulation of total BSP in both groups. The ratio of unconjugated BSP/BSP-GSH in the liver was about twice as high after pretreatment with iodomethane than in the control group.When BSP-GSH instead of BSP was infused, the excretion rates of this dye were identical in both groups. The maximal transport capacity (T_m) was double that observed with infusion of unconjugated BSP in control animals. There is indirect evidence that BSP and BSP-GSH might have different excretion pathways.     

Pharmacokinetic aspects of inorganic nitrate ingestion in man

Inorganic nitrate and nitrite concentrations were monitored simultaneously in the plasma, erythrocytes, saliva and urine of five subjects following an oral dose of NaNO3 (470 mumols per kg body weight). There was an average 25-fold increase in plasma nitrate only 10 min. after ingestion. Its concentration rose to a peak level of 1.83 mM in 40 min., a value 49 times the preload level. Erythrocyte nitrate followed a similar pattern, but remained at about two thirds of the plasma values. Salivary nitrate showed a positive correlation with plasma nitrate and averaged 9 times the plasma level during 3 hr following ingestion. This is evidence of a concentration-dependent active secretion by the salivary glands. The mean nitrate clearance was 25.8 +/- 2.85 (S.E.M.) ml/min. corrected for a body area of 1.73 m2 (n = 17). The urinary nitrate/creatinine ratio increased 25 to 70 times after loading. These results indicate a predominantly tubular excretion of nitrate. Nitrite was not detectable in any of the body fluids studied except saliva, where it appeared to increase at the expense of nitrate.     

Pharmacokinetic aspects of rectal formulations of Temazepam

An in vitro/in vivo study was carried out with different rectal formulations of temazepam. Pharmacokinetic data were determined in a cross-over study in 10 volunteers after rectal administration of 10 mg temazepam as a polyethylene glycol based suppository (selected from in vitro data), a liquid-filled capsule and a micro-enema respectively, using oral administration of a liquid-filled capsule as a reference. Serum levels of temazepam indicate an instantaneous and complete release from the micro-enema (F_rel=0.94±0.21, C_max 205±36.9 g/l, t_max 0.49±0.31 hour) and a slower but complete release of temazepam from the suppository (F_rel=1.01±0.25, C_max 202±41.3 g/l, t_max 1.48±0.41 hour). A high interindividual variation in absorption profiles was observed after rectal administration of the liquid-filled capsule (F_rel 0.72±0.36, C_max 182±122 g/l, t_max 4.08±4.28 hour), which makes it less suitable for rectal use. The micro-enema and suppository appear to be useful as rectal formulations for temazepam.     

非索非那定大鼠体内药代动力学研究

目的建立高效液相色谱法（HPLC）研究非索非那定灌胃给药后非索非那定体内药动学特点。方法采用HPLC测定,色谱柱为DikmaTMC18（4.6mm×250mm,5μm）,流动相：乙腈-0.5%磷酸二氢钾（pH3.8）-三乙胺（30∶70∶0.3）,流速：1.2ml/min,检测波长：220nm,检测非索非那定大鼠灌胃后药代动力学参数。结果非索非那定的药动学模型为二室模型,其药动学参数为Ka=1.689h-1,Cmax=1.225μg/ml,Tmax=1.8h,MRT=5.013h,t1/2α=1.018h。结论高效液相色谱法研究非索非那定大鼠灌胃给药后体内药代动力学,方法预处理简单、专属性强,结果可靠。