INFLUENCE OF CIMETIDINE COADMINISTRATION ON THE PHARMACOKINETICS OF SOTALOL ENANTIOMERS IN AN ANAESTHETIZED RAT MODEL: EVIDENCE SUPPORTING ACTIVE RENAL EXCRETION OF SOTALOL

Sotalol (STL) is an amphoteric, chiral β-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Cl_r) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg⁻¹) with cimetidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg⁻¹, n=7) immediately prior to the STL dose, or as a 30 mg kg⁻¹ bolus plus a 50 mg kg⁻¹ infusion over the 6 h study period (n=7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Cl_r by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Cl_r (R>S), and AUC (S>R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism, and that this system can be competitively inhibited by the presence of cimetidine.     

Stereospecific evaluation of sotalol pharmacokinetics in a rat model: Evidence suggesting an enantiomeric interaction

Sotalol (STL) is a chiral β-adrenergic blocking drug, which is useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S-enantiomer. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration-time profiles. Following administration of the pure S-enantiomer of STL, however, systemic clearance was significantly reduced; R-STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S-STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S-STL were significantly reduced from 33·7 ± 6·0 to 28·9 ± 5·6 ml min^?1 kg^?1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the β-blocking effects of R-STL may explain changes in S-STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.     

RENAL,BILIARY AND INTESTINAL CLEARANCE OF SOTALOL ENANTIOMERS IN RAT MODEL: EVIDENCE OF INTESTINAL EXSORPTION

Biliary clearance (Cl_b ) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague–Dawley rats (419±9 g, mean±SEM, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. Cl_b for S- and R-STL (0·0675±0·0090 and 0·0662±0·0089 mL min⁻¹ kg⁻¹, respectively) represented approximately 0·3% of systemic clearance (Cl_s ) values for S- and R-STL (20·4±2·2 and 20·7±2·0 mL min⁻¹ kg⁻¹, respectively). Bile:plasma concentration ratios at 1, 2, and 3 h post-dose were approximately 1·4, 1·3, and 1·2 for both STL enantiomers. Renal clearance (Cl_r ) and intestinal clearance (Cl_i ) of STL enantiomers were assessed in conscious Sprague–Dawley rats (325 g, n=4) following administration of a 10 mg kg⁻¹ IV dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine: Cl_r for S- and R-STL (26·3±3·2 and 28·7±4·2 mL min⁻¹ kg⁻¹, respectively) accounted for approximately 96% of Cl_s for S- and R-STL (27·5±3·3 and 29·9±4·2 mL min⁻¹ kg⁻¹, respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cl_i values of 1·16±0·17 and 1·26±0·19 mL min⁻¹ kg⁻¹ for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99·7±0·2 and 99·8±0·5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of intestinal exsorption of STL; (iii) STL does not appear to be metabolized; and (iv) Cl_s , Cl_r , Cl_b , and Cl_i are negligibly stereoselective.     

HPLC determination of ketoprofen enantiomers in human serum using a nonporous octadecylsilane 1.5 μm column with hydroxypropyl β-cyclodextrin as mobile phase additive

A sensitive and stereospecific high-performance liquid chromatography (HPLC) method for the quantitation of ketoprofen enantiomers in human serum was developed. The assay involves the use of an octadecylsilane solid-phase extraction for serum sample clean-up prior to HPLC analysis. Chromatographic resolution of the ketoprofen enantiomers was performed on a nonporous octyldecylsilane column with hydroxypropyl β-cyclodextrin as the mobile phase additive. The composition of the mobile phase was 98:2 v/v aqueous 0.1% trifluoroacetic acid (TFA), pH 4.00 (adjusted with triethylamine (TEA))/acetonitrile containing 10 mM hydroxypropyl β-cyclodextrin (β-CD) at a flow rate of 0.8 ml min⁻¹. Recoveries of R(−)-ketoprofen was 95.4±2.16% and for S(+)-ketoprofen 96.2±1.31%. Linear calibration curves were obtained in the range 0.025–15 μg ml⁻¹ range for each enantiomer in serum. The detection limit based on a S/N=3 ratio was 10 ng ml⁻¹ for each enantiomer in serum with ultraviolet detection at 220 nm. The limit of quantitation for each enantiomer was 25 ng ml⁻¹. Precision calculated as % relative standard deviation (%R.S.D.) and accuracy calculated as % error were in the range 0.2–5.2% and 0.3–2.2%, respectively, for the R enantiomer and 0.3–6.2 and 0.2–3.2%, respectively, for the S enantiomer.     

Further Characterization of the Solid Forms of Iopanoic Acid and its Enantiomers

The enantiomers of iopanoic acid were purified by crystallization and characterized by optical rotation, DSC, IR spectra, X-ray powder diffraction, and chiral HPLC. (-R)-enantiomer: [α]²⁰D = ?6.1°, mp. = 165.4°C; (+S)-enantiomer: [α]²⁰D = + 6.2°, mp. = 165.6°C. The IR spectra and X-ray patterns are fingerprints. Chiral HPLC (isocratic method, mobile phase: ethanol/n-hexane, 2/98 with 0.5% acetic acid) gave a resolution = 0.98 and a 99.6% recovery. From X-ray and thermal analyses the racemate Form I , mp. = 153.8°C, resulted to be a racemic compound. The binary phase diagram between the enantiomers and the racemic compound was constructed from the phase transition temp. obtained by DSC heating curves of appropriate mixtures. At a given enantiomer ratio (71/29) a eutectic compound, mp. = 144.7°C, is formed. In the range 88–100% a solid solution between the components is observed.     

PHARMACOKINETICS OF DA-125, A NEW ANTHRACYCLINE,AFTER INTRAVENOUS ADMINISTRATION TO URANYL NITRATE-INDUCED ACUTE RENAL FAILURE RATS OR PROTEIN--CALORIE MALNUTRITION RATS

The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg⁻¹, to control male Sprague--Dawley rats ( n=9) and uranyl nitrate-induced acute renal failure (U-ARF, n=12) rats, or male Sprague--Dawley rats fed on a 23% (control, n=8) or a 5% (protein--calorie malnutrition, PCM, n=9) protein diet. After i.v. administration of DA-125, almost ‘constant’ plasma concentrations of M1, M2, and M4 were maintained from 1--2 h to 8--10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1--M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUC_t values of M1 (115 against 82·5 μg min mL⁻¹), M2 (33·0 against 23·6 μg min mL⁻¹), and M4 (26·3 against 15·1 μg min mL⁻¹) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0·316%), M2 (under the detection limit against 5·58%), and M4 (0·0174 against 0·719%)---expressed in terms of DA-125---were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0·0532% against under the detcction limit), M3 (0·0286% against under the detection limit), and M4 (0·702% against 0·305%)---expressed in terms of DA-125---were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0·0320 μg mL⁻¹), M2 (0·0265 μg mL⁻¹), M3 (under the detection limit), and M4 (0·032 μg mL⁻¹) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.     

手性衍生化-反相高效液相色谱法测定大鼠肝微粒体中盐酸普罗帕酮对映体及其在代谢研究中的应用

目的　建立鼠肝微粒体中盐酸普罗帕酮消旋体(R/S-PPF)的手性拆分法,以研究大鼠肝微粒体中R/S-PPF体外代谢的立体选择性。方法　用GITC柱前手性衍生化、反相高效液相色谱法拆分R/S-PPF;外标法定量;体外微粒体孵育试验。结果　基线拆分了盐酸普罗帕酮两对映体,容量因子分别为7.9和9.5,分离系数α为1.2,分离度R为1.9,线性范围0.5～320 μg.mL^-1,检测限100 ng.mL^-1,定量限5 μg.mL^-1(RSD<15%)。平均绝对回收率S-PPF为77.1%,R-PPF为76.0%。平均日内、日间精密度均<10%。在DEX和BNF诱导鼠肝微粒体中,PPF的代谢呈显著的立体选择性,在空白对照微粒体中的代谢未呈立体选择性。结论　此法简便、经济,可用于鼠肝微粒体中R/S-PPF代谢的立体选择性研究。     

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg⁻¹ i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg⁻¹) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial p_CO2, p_O2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC_0–180 ), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (C_max=156± 6·5 ng mL⁻¹ against 51±5·8 ng mL⁻¹ in control; p<0·05). AUC_0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL⁻¹ min) than in control (6·8± 0·6 μg mL⁻¹ min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC_0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.     

Chiral discrimination of sibutramine enantiomers by capillary electrophoresis and proton nuclear magnetic resonance spectroscopy

Capillary electrophoresis (CE) and proton nuclear magnetic resonance spectroscopy (¹H-NMR) have been used to discriminate the enantiomers of sibutramine using cyclodextrin derivatives. Possible correlation between CE and ¹H-NMR was examined. Good correlation between the ¹H-NMR shift non-equivalence data for sibutramine and the degree of enantioseparation in CE was observed. In CE study, a method of enantiomeric separation and quantitation of sibutramine was developed using enantiomeric standards. The method was based on the use of 50 mM of phosphate buffer of pH 3.0 with 10 mM of methyl-beta-cyclodextrin (M-β-CD). 0.05% of LOD, 0.2% of LOQ for S-sibutramine enantiomer was achieved, and the method was validated and applied to the quantitative determination of sibutramine enantiomers in commercial drugs. On a 600 MHz ¹H-NMR analysis, enantiomer signal separation of sibutramine was obtained by fast diastereomeric interaction with a chiral selector M-β-CD. For chiral separation and quantification, N-methyl proton peaks (at 2.18 ppm) were selected because of its being singlet and simple for understanding of diastereomeric interaction. Effects of temperature and concentration of chiral selector on enantiomer signal separation were investigated. The optimum condition was 0.5 mg/mL of sibutramine and 10 mg/mL of M-β-CD at 10°C. Distinguishment of 0.5% of S-sibutramine in R-sibutramine was found to be possible by ¹H-NMR with M-β-CD as chiral selector. Host-guest interaction between sibutramine and M-β-CD was confirmed by ¹H-NMR studies and CE studies. A Structure of the inclusion complex was proposed considering ¹H-NMR and 2D ROESY studies.     

THE EFFECT OF FOOD ON THE PHARMACOKINETICS OF THE BICALUTAMIDE (‘CASODEX’) ENANTIOMERS

‘Casodex’ (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n =15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer C_max (734 ng mL⁻¹) was about nine times higher than the (S)-enantiomer value (84 ng mL⁻¹). The corresponding t_max values were 19 and 3 h for (R)- and (S)-bicalutamide respectively. Elimination of (R)-bicalutamide from plasma was monoexponential and slow (t_1/2=5·8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t_1/2=1·2 d; n =11). There was no significant effect of food on AUC, t_max, or t_1/2 data for either enantiomer. The observed slightly higher values of C_max for (R)-bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to be of any clinical relevance. These data indicate that ‘Casodex’ can be taken without reference to meal-times; this may be of particular relevance for its indication in a disease of the elderly. © 1997 John Wiley & Sons, Ltd.     

Serum protein binding of noscapine: Influence of a reversible hydrolysis

Abstract— The binding of the antitussive drug noscapine to human serum, pure albumin and α₁-acid glycoprotein has been investigated by ultrafiltration and equilibrium dialysis, using radiolabelled noscapine. The binding in serum pooled from volunteers was 93 ± 0.2% (at 100 ng mL^?1). After incubation for 24 h the binding decreased to about 85% (ultrafiltration 87.0 ± 1.0%; equilibrium dialysis 84.3 ± 1.2%), because of the conversion of noscapine to noscapinic acid. Only unbound drug underwent this hydrolysis, and as noscapine is extensively bound in healthy volunteers, this elimination process is probably unimportant. The major binding protein of noscapine was albumin (K = 3060 M^?1, n = 5.62), but the binding to ai-acid glycoprotein was also substantial (K = 31500 M^?1, n = 1.73). The interindividual variation in binding was low and binding was linear at the concentrations observed after therapeutic doses (0–500 ng mL^?1).     

VASOCONSTRICTOR RESPONSES TO POLYMORPHONUCLEAR LEUCOCYTES FROM ATHEROSCLEROTIC RABBITS

1. The vascular contractile effects of polymorphonuclear leucocytes (PMN) isolated from control rabbits and from rabbits made atherosclerotic by 1% cholesterol feeding for 8 weeks were examined. 2. Rings of control rabbit thoracic aorta with or without endothelium were mounted at 2g tension in 10 mL organ baths and were submaximally contracted by phenylephrine (0.1 μmol/L). After 30 min incubation at 37° C, the supernatant of PMN (5X10⁷/mL, in Tyrode solution containing 0.25% bovine serum albumin) was obtained by centrifugation for addition to the vascular preparation. 3. Control PMN supernatant (443 μL) caused contraction (0.58±0.15g, n= 11) of phenylephrine-contracted aortic rings, which was prevented by removal of the endothelium (0.11 ± 0.07g, n= 5, P<0.05). However, the control PMN supernatant had no contractile effect on aortic rings at resting tension (0.00 ± 0.00g, n= 8). 4. By comparison, atherosclerotic PMN supernatant (443 μL) caused a significantly greater contraction of the aortic rings (1.41± 0.13g, n= 9, P<0.05 vs control PMN supernatant) that was only partly inhibited by removal of the endothelium (0.45 ± 0.20g, n= 9, P<0.05). Moreover, PMN supernatants from four of seven atherosclerotic rabbits contracted aortic rings at resting tension (3.5 ±1.4g, n= 7). 5. These results suggest that the release of a stable vasoconstrictor substance(s) by PMN is enhanced under conditions of atherosclerosis. The constrictor action of this substance(s) appears to be greater in the presence of a functional endothelium, and part of its action may involve inactivation of endothelium-derived nitric oxide.     

The action of flecainide acetate and its enantiomers on mammalian non-myelinated nerve fibres

The effects of flecainide acetate racemate and its two enantiomers on voltage-operated sodium and potassium channels and on the sodium pump activity of non-myelinated fibres of the guinea-pig vagus nerve were studied with the sucrose-gap method. The racemic mixture as well as theR enantiomer andS enantiomer in a concentration range of 3·10^?5?3·10^?4 M caused suppression of the compound action potential, a diminished propagation velocity and a reduction of the post-tetanic potential (PTH), which was also observed with lidocaine. There was no significant difference in the effect caused by the enantiomers seperately. TheR enantiomer tended to evoke a stronger effect compared with theS enantiomer. However, the magnitude of the action is concentration-dependent. At a concentration<10^?4 M the action of the racemate was stronger than an equimolar concentration of the enantiomers. The activity of the sodium pump, defined by the time constant of post-tetanic potential decay, was affected at a concentration of 10^?4 M of the racemate, in contrast to lidocaine. The racemate and both enantiomers of flecainide acetate possess a similar local anaesthetic action, as reflected by the inhibition of voltage-operated sodium channels.     

川芎中川芎嗪和阿魏酸含量的毛细管电泳测定

目的：研究川芎中川芎嗪和阿魏酸的毛细管电泳分离分析的可行性。方法：通过用毛细管区带电泳分离、紫外检测模式研究内标、电泳缓冲液、进样方式、分离电压等对样品中川芎嗪和阿魏酸分离与定量的影响,优化实验条件。结果：以对硝基苯甲酸为内标,未涂层熔融石英毛细管(39.5 cm×50 μm ID,有效分离长度34.8 cm)为分离通道,30 mmol.L^-1硼砂缓冲液(pH 9.43)为电泳介质,34 kPa.s压力进样,17 kV分离电压,295 nm检测,川芎嗪和阿魏酸分别在7～423 μg.mL^-1和4～900 μg.mL^-1范围内可进行定量检测,回收率分别为100.9％±1.9％和99.8％±1.0％。结论：毛细管电泳法可用于川芎中川芎嗪和阿魏酸的同时分离分析。     

反式曲马多对映体的药代动力学立体选择性

目的:研究反式曲马多对映体:( + )-反式曲马多和( - )-反式曲马多的人体药代动力学。方法:12 名受试者po 多剂量盐酸反式曲马多缓释片,用高效毛细管电泳法测定人血清中反式曲马多对映体的浓度,配对t-检验比较两对映体的血药浓度和药代动力学参数。结果:血药浓度达稳态后不同时间血清中( + )-反式曲马多的浓度均明显高于( - )-反式曲马多的浓度,两对映体的C_max,C_min ,C_av,AUC_0→∞,T_1/2 等药代动力学参数均有显著性差异。结论:人体对( + )-反式曲马多比对( - )-反式曲马多吸收完全、消除慢,反式曲马多对映体有药代动力学立体选择性。     

Pharmacokinetics:Pharmacokinetic Differences Between Lansoprazole Enantiomers in Rats

Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats. There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg^?1) to rats. C_max (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5–6 times greater than those for (—)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (—) enantiomer. CL_tot/F values (where CL_tot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (—) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (—) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (—)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 μM lansoprazole. These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.     

Effects of turpentine oil pretreatment on β-blocker pharmacokinetic parameters in rats

Abstract— Turpentine oil treatment (0·2 mL kg^?1, s.c.) was used to increase the plasma concentration of α₁-acid glycoprotein (0·13 mg mL^?1 in control rats) to 1·72 mg mL^?1 after 2 days, and allow assessment of its effects on the pharmacokinetics and stereoselective binding of three β-blockers. Racemates (5 mg kg^?1) were administered intravenously to control and turpentine oil-pretreated rats and the plasma concentrations were determined up to 90 min. Stereoselective analysis showed the apparent distribution volume and the area under plasma concentration-time curves (AUC) of R-(+)-propranolol to be, respectively, one-quarter and twice those of the S-(–)-enantiomer and differences in pharmacokinetic parameters between the two were magnified by turpentine oil pretreatment. Pharmacokinetic parameters of oxprenolol enantiomers were essentially similar for the controls but after turpentine oil pretreatment, a higher affinity of the R-(+)-enantiomer for plasma was observed. Acebutolol enantiomers behaved non-stereospecifically throughout. These results were consistent with predictions from the in-vitro stereospecific binding properties of these agents to purified rat α₁-acid glycoprotein.     

Separation of carnitine enantiomers as the 9-anthroylnitrile derivatives and high-performance liquid chromatographic analysis on an ovomucoid-conjugated column

9-Anthroylnitrile was used as an achiral reagent for the derivatization of carnitine. The reagent forms UV-absorbing derivatives with the hydroxyl groups of carnitine enantiomers under very mild conditions. The derivatives were separated by high-performance liquid chromatography on an ovomucoid-conjugated column with a mobile phase of acetonitrile-20 mM KH ₂ PO ₄ (adjusted to pH 4.5 with phosphoric acid) (17:83, v/v). The separation factor (α) and resolution ({ce:inline-formula}R _s{/ce:inline-formula}) of the enantiomers were 1.44 and 5.05, respectively. The calibration plots indicated good linearity over a sample concentration ranging from 0.2 to 1.0 mg ml ⁻¹, and the detection limit at 254 nm was 0.05 mg ml ⁻¹ for each carnitine enantiomer. The reproducibility in the analysis of 1 mg ml ⁻¹ of each enantiomer was within 2.0%. The method was applied successfully to the determination of carnitine enantiomers in pharmaceutical preparations.     

Antihypertensive and Biochemical Effects of Indacrinone Enantiomers

The enantiomers of indacrinone (I), an investigational loop diuretic, have different pharmacologic activity. The (–) enantiomer is natriuretic, and the (+) enantiomer is uricosuric. To determine the antihypertensive effects and an isouricemic ratio of indacrinone enantiomers, 37 patients with sitting diastolic blood pressure (BP) between 90 and 104 mm Hg, after a 4-week placebo washout, randomly received one of the ratios of I enantiomers, namely −2.5/ + 80 mg (A), −5/ + 80 mg (B), −10/ + 80 mg (C) or placebo (P), once daily for 12 weeks in a double-blind, parallel study. The mean reductions (baseline-end of treatment) in BP of 23/8, 20/10 and 25/10 mm Hg with treatments A, B and C respectively were greater (p < 0.01) than that on P (0/3). Initially, serum uric acid decreased with treatments A and B but not with C. Mean changes in serum uric acid were −0.3, −0.4, 0.2 and 0.3 mg/dl respectively with treatments A, B, C and P. The ratio of −10/+ 80 mg produced least variation in serum uric acid. Reduction in serum K⁺ and Cl⁻ appeared to be dose related to (–) enantiomer. No serious adverse effects were reported. A 1:9 ratio of I enantiomers intended for wide-scale use as a diuretic also showed good antihypertensive activity, a favorable uric acid profile and absence of hepatic toxicity in 14 patients.     

THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for C_min (mean (SD)=47·2 (25·8) against 39·6 (21·1) ng mL⁻¹, p=0·038), AUC_0–24 (2008 (814) against 1754 (714) ng h mL⁻¹, p=0·024), and AUC_0–48 (2662 (1244) against 2395 (238) ng h mL⁻¹, p=0·034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.