Effect of hyperlipidemia on ketoconazole-midazolam drug-drug interaction in rat

Hyperlipidemia (HL) was previously shown to lower liver uptake of the more potent (-) enantiomer of ketoconazole (KTZ) in rat. The current study examined the possible modifying influence of experimental HL on a KTZ pharmacokinetic interaction with midazolam (MDZ). Normolipidemic and hyperlipidemic rats were administered a single intravenous dose of MDZ (5 mg/kg) with or without a single oral dose of racemic KTZ (40 mg/kg). Serial blood samples were collected over 8 h following MDZ injections via jugular vein cannulas. Plasma was jointly assayed for MDZ and KTZ concentrations using a validated assay. MDZ mean clearance (CL) was unchanged by KTZ coadministration. HL caused a significantly 61% lower MDZ-unbound fraction and decreases in volume of distribution (VD) but by itself had no effect on MDZ CL. This suggested that MDZ could bind to lipoproteins. With KTZ coadministered to hyperlipidemic rats, there were significant decreases in MDZ CL and VD. HL caused a decrease in unbound plasma fraction of oral KTZ but no significant difference in its pharmacokinetics. HL caused a more pronounced KTZ-associated inhibition of MDZ CL. This may be related to the decrease of MDZ's unbound fraction and perhaps to attenuation of CYP3A by HL in the rat.     

Stereoselective pharmacokinetics of desbutylhalofantrine, a metabolite of halofantrine, in the rat after administration of the racemic metabolite or parent drug

The main objective of this study was to determine the pharmacokinetics of the enantiomers of desbutylhalofantrine (DHF), a metabolite of halofantrine (HF), in the rat. Rats received either intravenous (2 mg/kg) or oral (7 mg/kg) (+/-)-DHF HCl, or (+/-)-HF HCl intravenously (3 mg/kg). Enantiomer concentrations in plasma were determined by a stereospecific assay. In all rats, the plasma concentrations of (+)-DHF exceeded those of (-)-DHF. After (+/-)-DHF, the mean (+):(-) ratios of AUC(0-infinity) after oral and intravenous dosing were 3.7 and 2.8, respectively. After intravenous doses of DHF, the (-):(+) enantiomeric ratios of Cl and V(dss) were approximately 2.8. There were no significant differences between the enantiomers in t(1/2) (mean 14-23 h) or t(max) (mean 10-12 h) after intravenous or oral administration of DHF. Oral bioavailability estimates of DHF enantiomers (>59%) were higher than those previously estimated for HF in the rat. The stereoselectivity in HF kinetics was not as pronounced as for DHF. It was estimated that over 44% of the dose of HF is metabolized to DHF enantiomers. It was concluded that DHF possesses a pharmacokinetic profile similar to that of HF, each possessing low values of clearance and high volume of distribution. DHF differed from HF in its degree of stereoselectivity in pharmacokinetics, and in its extent of oral bioavailability.     

The pharmacokinetics of etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers

Pharmacokinetics of the enantiomers of the nonsteroidal anti-inflammatory drug etodolac (ET, (+/- )-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid), which is marketed as a racemate, were studied in male Sprague-Dawley rats. Following administration of iv racemate, plasma concentrations of inactive R-ET were much greater than those of active S-ET. After iv doses of individual enantiomers, similar results were found, with significantly greater t1/2, CL, and Vdss, and lower AUC, for S- than for R-ET. No evidence of a pharmacokinetic interaction between the enantiomers was observed. Secondary peaks indicative of extensive enterohepatic recirculation were seen in plasma time courses of S-ET. In bile duct-cannulated rats, the AUC of S- but not R-ET, was significantly reduced, and secondary peaks were absent in plasma profiles. The differences between enantiomers were attributed to a greater extent of plasma protein binding of R-ET, and to preferential conjugation and biliary excretion of S-ET. Complete recovery of S-ET was achieved in bile, whereas only 30% of the R-enantiomer was recovered via this route of elimination. Urine was a minor route of elimination of ET. It was concluded that the rat may be a suitable pharmacokinetic model for the study of stereoselective pharmacokinetics of ET because, in some aspects, the results closely paralleled those of ET in man.     

Pharmacokinetics and allometric scaling of levormeloxifene,a selective oestrogen receptor modulator

The pharmacokinetics of a new selective oestrogen receptor modulator levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(V(ss)/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(V(c)/F) and volume at steady state F(V(ss)/F) were 28.9 and 57.9 l, respectively. In humans, values of V(c)/F and V(ss)/F were 106 and 587 l, respectively. Predicted CL/F and V(ss)/F showed a linear relationship when plotted vs BW on a log-log scale; for CL/F, r was 0.95-0.98 and for V(ss)/F, r was 0.99. Using allometric scaling the predicted human V(ss)/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21-25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods.     

Effect of alpha(1)-acid glycoprotein on the pharmacokinetics of tamsulosin in rats treated with turpentine oil

The pharmacokinetics of tamsulosin (TAM) was investigated using male Sprague-Dawley rats in which plasma alpha(1)-acid glycoprotein (alpha(1)-AGP) levels were elevated by the subcutaneous injection of 0.2 mL/kg of turpentine oil. alpha(1)-AGP levels increased about eight times after turpentine oil treatment, causing a threefold decrease in plasma unbound fraction (f(u)) of TAM. When 0.3 mg/kg of TAM was dosed intravenously, total and nonrenal clearances (CL(tot) and CL(nr)) in turpentine-treated rats were 47% and 44% lower than those in nontreated controls, respectively. The area under the concentration-time curve of plasma unbound TAM (AUC(inf,u)) was lower than that in the control. When 1 mg/kg of TAM was dosed orally, oral clearance (CL(oral)) in alpha1-AGP-induced rats was 65% lower than in the control. The AUC(inf,u) and unbound oral clearance (CL(oral,u)) were nearly equal in both groups. Moreover, a positive correlation was observed between fu and CL(oral) of TAM (r(2) = 0.603, P < 0.01), whereas no correlation was observed between f(u) and CL(oral,u). The absolute bioavailability (BA) increased from 19.2% to 46.9% by induction of alpha(1)-AGP. These results suggest that decreased f(u) caused by the elevation of plasma alpha(1)-AGP level affects the pharmacokinetics of TAM, but does not affect the CL(oral,u,) which represents the hepatic metabolism of TAM.     

Stereoselective distribution and stereoconversion of zopiclone enantiomers in plasma and brain tissues in rats

Concentrations of (-)-zopiclone and (+)-zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)-zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (-)-zopiclone, both enantiomers were found in plasma and brain with (+)-zopiclone/(-)-zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.     

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.     

Effects of poloxamer 407-induced hyperlipidemia on the pharmacokinetics of carbamazepine and its 10,11-epoxide metabolite in rats: Impact of decreased expression of both CYP3A1/2 and microsomal epoxide hydrolase

The pharmacokinetics of carbamazepine (CBZ) and its active 10,11-epoxide metabolite (CBZ-E) were evaluated after intravenous and oral administration of 5 mg/kg CBZ to rats with hyperlipidemia induced by poloxamer 407 (HL rats) and controls. The total area under the plasma concentration-time curve (AUC) of CBZ in HL rats after intravenous administration was significantly greater than that in controls due to their slower non-renal clearance (CL(NR)). This was due to slower hepatic CL(int) for metabolism of CBZ to CBZ-E in HL rats via CYP3A1/2. This result was consistent with a previous study indicating reduced hepatic CYP3A1/2 expression in HL rats. Interestingly, the AUC of CBZ-E was also increased in HL rats, while AUC(CBZ-E)/AUC(CBZ) ratios remained unchanged. These results suggested that further metabolism of CBZ-E to the inactive metabolite trans-10,11-dihydoxyl-10,11-dihydro-CBZ (CBZ-D) via microsomal epoxide hydrolase (mEH) was also slowed in HL rats. The significantly reduced hepatic mRNA level and expression of mEH protein in HL rats compared to controls confirmed the above hypothesis. Similar pharmacokinetic changes were observed in HL rats after oral administration of CBZ. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Caution is required regarding pharmacotherapy in the hyperlipidemic state in cases where drugs that are metabolized principally by CYP3A1/2 or mEH and have a narrow therapeutic range are in use.     

Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs.

The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P(tp)) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V(ss)). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P(tp) data (method Vd2). Best V(ss) predictions were obtained using method Vd2, providing that rat P(tp) input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V(ss) predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.     

Assessment of glibenclamide pharmacokinetics in poloxamer 407-induced hyperlipidemic rats

The aim of the present research was to describe the consequences of hyperlipidemia (HL) on the pharmacokinetics of glibenclamide (Gb) in poloxamer 407-induced hyperlipidemic rats. Rats were given intraperitoneal dose of poloxamer 407 to cause hyperlipidemia. A single oral dose of Gb (10 mg/Kg) was given to normal and HL rats. The C_max and t_max after oral dose of Gb in normal rats were 340.10 µg/ml and 3.67 h, respectively. Whereas, the C_max and t_max after oral dose of Gb in HL rats were noted as 773.39 µg/ml and 2.50 h respectively. The AUC value of Gb was found considerably higher in the HL rats. While the plasma clearance (CL) after oral dose of Gb was 2.53 ml/h and 1.39 ml/h in normal and HL rats respectively. The improved plasma concentration of Gb following oral dosing in rats with HL seems to be due to a direct influence on hepatic clearance or metabolizing enzymes. In conclusion, the Gb pharmacokinetics was considerably affected by the HL in rats. Such findings play an important role for predicting the alterations in the pharmacokinetics of drugs including GB, in cases having hyperlipidemia.     

Stereoselectivity in the metabolism of disopyramide enantiomers in rat and dog

The metabolism and pharmacokinetics of (S)-(+)- and (R)-(-)-disopyramide (DP) were compared in laboratory animals. In rats, after oral administration of (S)-(+)-DP phosphate salt at a dose of 38.8 mg of DP free base per kg, the mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.43 micrograms/ml and 4.47 micrograms . hr/ml, respectively, and after (R)-(-)-DP administration, the values were 4.93 micrograms/ml and 17.05 micrograms . hr/ml, respectively. Similar recoveries (approximately 55% of the dose) of DP and its metabolites in the urine and bile of rats were obtained after administration of the individual (S)-(+)- and (R)-(-)-enantiomers of DP. These results indicate similar oral absorption of the two enantiomers, but greater metabolism with (S)-(+)-DP in rats. In dogs, the AUC of DP after iv administration of (R)-(-)-DP phosphate salt at a dose of 15 mg of DP free base per kg was 1.6 times greater than that after (S)-(+)-DP phosphate salt. Inasmuch as volumes of distribution of the two enantiomers were similar, this difference can be attributed to a difference in the elimination rates of the enantiomers. After an oral dose, the difference in AUC of the two enantiomers was greater than that after an iv dose. The mean values of Cmax and AUC after a 15-mg/kg oral dose of (S)-(+)-DP were 1.32 micrograms/ml and 4.07 micrograms . hr/ml, respectively, and with (R)-(-)-DP the values were 2.88 micrograms/ml and 9.21 micrograms . hr/ml, respectively. The Cmax and AUC of the total drug-related materials (drug plus its metabolites) were similar. These results, together with the similarity in the urinary excretion of total drug related compounds, indicated that after equivalent doses of the two enantiomers, oral absorptions were similar, but the first-pass metabolism was greater with (S)-(+)-DP. The present study also demonstrated that N-dealkylation in dogs and arylhydroxylation in rats are stereoselective metabolic pathways, thus illustrating species differences in the stereoselective metabolism of DP.     

Enantioselective pharmacokinetics of etodolac in the rat: tissue distribution, tissue binding, and in vitro metabolism.

The nonsteroidal anti-inflammatory agent etodolac (ET) exhibits stereoselectivity in its pharmacokinetics following administration to humans and rats. To underline the factors responsible for this stereoselectivity, the tissue distribution, in vitro tissue binding, and microsomal metabolism of ET enantiomers were studied in the rat. Following iv administration of racemic ET, the S:R AUC ratios in tissues were stereoselective, and different from that in plasma. Binding of enantiomers to tissues was stereoselective, although it did not relate well with in vivo tissue distribution. Rather, the tissue distribution of enantiomers appeared to be better explained by the unbound fractions of enantiomers in plasma. With respect to in vitro glucuronidation by liver microsomes, the Vmax of S-ET was 3.4-fold greater than that of R-ET; the enantiomers possessed similar Km. There appeared to be stereoselectivity in the oxidative metabolism of ET enantiomers by liver and kidney microsomes, in favor of the R-enantiomer. The lower AUC in rat plasma of pharmacologically active S-ET as compared with its antipode is due to its relatively greater distribution to tissues, owing to a lesser degree of binding to plasma proteins, and to its higher rate of glucuronidation.     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

Sex-related differences in the pharmacokinetics of oral ciprofloxacin

The oral pharmacokinetics of ciprofloxacin were studied in healthy volunteers to assess the influence of sex on its disposition. Subjects (8 males, 7 females) received a single oral dose of ciprofloxacin 750 mg, blood and urine samples were collected, and ciprofloxacin concentrations were determined. A two-compartment open-model with two or three absorption phases, each one having a fitted independent lag time, best fit the data using a weighted least squares estimator. Univariate and multivariate regression analyses were performed to determine the influence of renal function, weight, and subject sex on the oral clearance (CL(S)/F) and apparent steady-state volume of distribution (V(ss)/F) of ciprofloxacin. Females had a median C(max) of ciprofloxacin that was 30% greater than males and a significantly smaller median (range) V(ss)/F: 81.1 (44.8-111.6) versus 170.9 (140.9-213.4), respectively (p < 0.01). In addition, females had increased exposure to ciprofloxacin, with a slower median (range) CL(S)/F of 28.3 L/h (24.5-33.4) compared to 44.4 L/h (41.4-53.7) for males (p < 0.01). Regression analyses revealed that subject sex was the only significant predictor of CL(S)/F (p < 0.001), but both body weight (p = 0.04) and subject sex (p < 0.005) were significant predictors of V(ss)/F. Fixed oral doses of ciprofloxacin will lead to higher maximum concentration and total drug exposure in females compared to males and do not appear to be solely related to weight-based differences.     

Stereoselective pharmacokinetics of flurbiprofen in humans and rats

Flurbiprofen, a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), exists as racemate and is used as such. Although the activity of 2-APAs is due mainly to their S-enantiomers, information on the pharmacokinetics of flurbiprofen is usually based on the measurement of total concentrations of S- and R-flurbiprofen. In this work, the pharmacokinetics of flurbiprofen enantiomers following single doses were studied in humans and rats. Upon iv administration of 10 mg/kg of racemic flurbiprofen to male Sprague-Dawley rats, the plasma concentrations were consistently higher for S-flurbiprofen than for R-flurbiprofen (AUC = 134 +/- 39 versus 41 +/- 9 mg.L-1 h). In bile duct-cannulated rats, the biliary excretion contained only 3.6-5.2% of the dose as conjugated flurbiprofen (S:R = 1.2-2.1). After administration of R-flurbiprofen to the rat, both enantiomers were found in plasma [AUC(R):AUC(S) = 0.10-0.16], indicating a limited extent of enantiomeric bioinversion. This is consistent with the previously reported limited extent of flurbiprofen uptake into fat. In healthy volunteers also, significant stereoselectivity was observed in the plasma concentration of the drug after 100-mg oral racemic doses [AUC-(S):AUC(R) = 45.4 +/- 12.7:40.1 +/- 14.3 mg.L-1.h]. As compared with the R-enantiomer, S-flurbiprofen has a smaller volume of distribution (7.23 +/- 1.9 versus 8.41 +/- 3.0 L) and total clearance (1.23 +/- 0.34 versus 1.47 +/- 0.50 L/h), but an equal half-life (4.21 +/- 1.2 versus 4.18 +/- 1.3 h). In urine, on the other hand, the R-configuration was predominant, as greater amounts of the R-enantiomer were found both as conjugated flurbiprofen and as an unidentified metabolite. Negligible amounts of intact flurbiprofen enantiomers were detected in urine. The observed stereoselectivity in humans cannot be attributed to enantiomeric bioinversion, as S-flurbiprofen was not detected in plasma and urine after oral administration of R-flurbiprofen.     

Selective Effect of Adjuvant Arthritis on the Disposition of Propranolol Enantiomers in Rats Detected Using a Stereospecific HPLC Assay

Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.     

Brain pharmacokinetics and tissue distribution of tetrahydropalmatine enantiomers in rats after oral administration of the racemate

Tetrahydropalmatine (THP), a racemic mixture, is a biologically active ingredient isolated from a traditional Chinese herb Rhizoma Corydalis (yanhusuo). The main objective of this study was to determine the brain pharmacokinetics and tissue distribution of THP enantiomers in rats after oral administration of racemic THP (rac-THP). Rats (5 animals/group/per time) were given a single oral dose of rac-THP and killed after different post-treatment times. The concentrations of THP enantiomers in plasma, cortex, cerebellum, diencephalon, brain stem, striatum and hippocampus were measured using a validated chiral high performance liquid chromatographic (HPLC) method coupled with an achiral column. The pharmacokinetic profiles of the two enantiomers in six brain regions were significantly different. The peak concentrations (Cmax) and AUC(0-infinity) values of the (-)-enantiomer were significantly greater than the corresponding values for the (+)-enantiomer while the striatum contained the highest peak concentrations compared with the plasma and other brain regions. The tissue distribution studies also revealed significant differences between the two enantiomers in all tissues except the lung. The highest concentrations of both enantiomers were found in the liver. The (-)/(+)-THP ratios in six brain regions and other tissues were consistent with that observed in plasma indicating that the stereoselective disposition of THP in rat brain and other tissues reflects the situation in plasma.     

The effect of experimental hyperlipidemia on the stereoselective tissue distribution, lipoprotein association and microsomal metabolism of (+/-)-halofantrine

The effect of hyperlipidemia on the biodistribution of (+/-)-halofantrine (HF) was studied in rats. Plasma, adipose, and highly perfused tissues heart, lung, liver, kidney, spleen and brain were harvested for up to 48 h after dosing animals with 2 mg/kg (+/-)-HF intravenously by tail vein. Stereospecific HPLC was used to measure HF and desbutyl-HF (DHF) enantiomer concentrations. Plasma concentrations of both HF enantiomers in hyperlipidemic (HL) exceeded those in normolipidemic (NL) rats by 11- to 15-fold. Significant increases in AUC of both HF enantiomers were noted in HL spleen tissue whereas decreases were seen in HL lung and fat. In rest of the tissues either decreases or no changes were noted in HL. The concentrations of DHF were very low in NL and HL plasma but were much higher in all highly perfused tissues. Both HF and DHF enantiomers shifted from lipoprotein deficient fraction to triglyceride-rich fractions in HL plasma following in vitro incubation of the respective racemic compounds. Compared to NL, no significant differences were noted in HF metabolism to DHF in HL liver microsomes. It would appear that both reduced plasma unbound fraction and lipoprotein associated directed uptake of lipoprotein-bound drug by tissues play roles in enantiomer biodistribution.     

氯苯氧异丁酸甲氧基苯丙烯酸酯代谢物在大鼠体内的药动学

目的:研究不同剂量氯苯氧异丁酸甲氧基苯丙烯酸酯{(E)-3-[4-[2-(4-chlorophenoxy)-2-methylpropanoyloxy]-3-me-thoxyphenyl]acrylic acid,AZ}灌胃给药后活性代谢产物氯苯氧异丁酸在大鼠体内药动学。方法:3组大鼠按体质量分别灌胃给予125,250,500 mg.kg-1的AZ后,以布洛芬为内标物,采用高效液相色谱法测定代谢产物氯苯氧异丁酸的血药浓度,各组结果分别用DAS 2.0软件进行药动学分析,组间药动学参数用SPSS11.5软件进行统计分析。结果:低、中剂量组氯苯氧异丁酸的t1/2,CL/F,MRT均无显著性差异,AUC随给药剂量增加线性增大。高剂量组与中剂量相比,t1/2变大,CL/F显著减小,MRT显著延长。结论:口服AZ在125～250 mg.kg-1剂量时,其代谢产物氯苯氧异丁酸在大鼠体内符合线性动力学过程,剂量在500 mg.kg-1以上时则表现为非线性动力学特征。     

Distribution of gacyclidine enantiomers after experimental spinal cord injury in rats: possible involvement of an active transport system

The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (+/-)-gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography-mass spectrometry (GC-MS) assay. In plasma, concentrations of (+)-gacyclidine were approximately 25% higher than those of (-)-gacyclidine over the duration of the experiment and decayed in parallel (t(1/2 alpha) approximately 7 min; t(1/2 beta) approximately 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (-)-gacyclidine were approximately 20% higher than those of its optical antipode (CL: 285 versus 236 mL. kg(-1). min(-1); Vd(beta): 39.3 versus 31.2 l/kg). Protein binding (approximately 91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (-)-gacyclidine was, however, significantly higher (approximately 30%) than that of (+)-gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF.