Nuggehally R. Srinivas

Enantioselective pharmacokinetics and pharmacodynamics of dl‐thero‐mcthylphenidate in children with attention deficit hyperactivity disorder

Nine boys with attention‐deficit hyperactivity disorder took part in a study in which d‐methylphenidate, l‐methylphenidate, dl‐methylphenidate, or placebo were administered in a double‐blind, four‐way, randomized, crossover design. Plasma levels of the isomers of methylphenidate were monitored by means of an enantioselective assay method. The ability of the children to perform tasks that required sustained attention was monitored by a battery of computer tests. There was no evidence of interconversion between the enantiomers in vivo, although the presence of the d‐isomer significantly altered the pharmacokinetics of the l‐antipode. The presence of the l‐isomer did not affect the pharmacokinetics of d‐methylphenidate. The computer tests revealed a drug‐induced improvement in sustained attention that was entirely attributable to the d‐enantiomer. There was no evidence to suggest that the effectiveness of d‐methylphenidate was in any way compromised by the presence of its antipode.

Enantioselective Pharmacokinetics of dl-threo-Methylphenidate in Humans

A definitive enantioselective pharmacokinetic evaluation of dl-threo-methylphenidate (MPH) was carried out in 11 healthy volunteers, all of whom received, in a randomized crossover design, three oral administrations of MPH: immediate release (IR), slow release (SR), and SR chewed before swallowing (CH). In addition, all subjects received MPH intravenously (IV) on a separate occasion. Both plasma and urine samples were collected for up to 16 hr after each drug administration. Significant enantioselective differences were found in pharmacokinetic parameters such as CL, MRT, Vdss, AUC0∞, and t1/2. A profound distortion of the enantiomeric ratio for MPH (d ≫ 1) was evident in all plasma samples harvested after oral administration. After IV MPH, however, there was no significant distortion in the plasma d/1 ratio until 1.5 hr after dosing, whereafter there was a divergence of the plasma levels of the enantiomers. After oral administration of dl-MPH, the absolute bioavailability (F) of d-MPH was 0.23 and that of l-MPH was 0.05. There were no significant differences in renal clearance for d- or l-MPH after oral or IV administration, although the fraction of the dose excreted unchanged in the urine was significantly greater after IV MPH. These data suggest that enantioselective differences in the pharmacokinetics of oral MPH are the result of enantioselectivity in presystemic metabolism rather than in renal excretion, such that l-MPH is preferentially converted into l-ritalinic acid. Finally, it was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.

Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans

1. Two pilot studies were carried out to investigate the enantioselective pharmacokinetics of methylphenidate (MPH) in children with attention deficit-hyperactivity disorder (ADHD). A more definitive study, which included administration of an intravenous dose, was carried out in healthy young men. 2. Serial plasma samples were harvested from predose to 8 hours in the first pilot study, predose to 12 hours in the second pilot study and predose to 16 hours in the definitive study. Plasma levels of the separate isomers d-MPH and 1-MPH were determined by an enantioselective gas chromatographic method. 3. In the first pilot study, 6 boys with ADHD each received his regular dose of MPH (10mg n = 5, 5mg n = 1), which contained equal proportions of d-MPH and 1-MPH in an immediate release formulation (MPH-IR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 4 to 10 fold higher than those of 1-MPH. Plasma levels of 1-MPH were so low that it was not possible to monitor them beyond 4 hours in some children. 4. In the second pilot study, 5 boys and 1 girl with ADHD each received their regular dose (20mg) of a slow release formulation (MPH-SR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 5 to 10 fold higher than those of 1-MPH. It was possible to monitor plasma levels of 1-MPH over the full 12 hour period of study in 5 of the 6 children.(ABSTRACT TRUNCATED AT 250 WORDS)

Enantioselective gas chromatographic assay with electron-capture detection for dl-ritalinic acid in plasma.

Enantioselective gas chromatographic assays for the quantitation of methylphenidate and its major metabolite ritalinic acid in plasma are described. The procedures involved the extraction of methylphenidate enantiomers from alkanised plasma. The plasma was then washed to ensure complete removal of methylphenidate before saturation with sodium carbonate to promote the extraction of ritalinic acid enantiomers with ethyl acetate-isopropanol (60:40) solvent mixture. Subsequently, ritalinic acid enantiomers were converted back into methylphenidate enantiomers by Fisher-Speier esterification. N-Heptafluorobutyryl-L-prolyl chloride, a chiral acylating reagent, was used to convert the enantiomers of methylphenidate into their corresponding diastereomeric amide derivatives, which were separated cleanly on an achiral capillary column (OV-225) and quantitated with electron-capture detection. The assays were sensitive, reliable and reproducible.

Enantioselective gas chromatographic assays with electron-capture detection for methoxyphenamine and its three primary metabolites in human urine.

Sensitive and enantioselective gas chromatographic assays have been developed and applied to the quantitation in human urine of the enantiomers of methoxyphenamine and its three primary oxidative metabolites, namely, N-desmethylmethoxyphenamine, O-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine. The separation of the various analytes was achieved through the combined use of high-resolution gas chromatography coupled with electron-capture detection and employing a capillary OV-225 column. The formation of diastereometric derivatives involved the chiral acylating reagent N-heptafluorobutyryl-L-prolyl chloride. The assays for methoxyphenamine and O-desmethylmethoxyphenamine were linear over the range 0.25-2.0 micrograms/ml for each analytes enantiomers, while in the case of the enantiomers for N-desmethylmethoxyphenamine and 5-hydroxymethoxyphenamine linearity was shown over the ranges 0.094-0.75 and 0.188-1.5 micrograms/ml, respectively. The mean coefficients of variation in all cases were less than 4%.

Enantioselective gas chromatographic assay with electron-capture detection for dl-fenfluramine and dl-norfenfluramine in plasma.

An enantioselective gas chromatographic assay utilising electron-capture detection has been developed for the simultaneous quantitation of enantiomers of fenfluramine and nonfenfluramine in plasma. The assay involves the conversion of the enantiomers of both fenfluramine and norfenfluramine into their corresponding diastereomeric amide derivatives by an acylation reaction with n-heptafluorobutyryl-S-prolyl chloride under Schotten-Baumann conditions prior to gas chromatographic separation on an achiral polar OV-225 capillary column. Linear and reproducible standard curves were obtained over the concentration ranges 4.30-86.3 ng/ml per enantiomer and 1.25-42.25 ng/ml per enantiomer for the enantiomers of fenfluramine and norfenfluramine, respectively. The method was applied to a single-dose pharmacokinetic study in a healthy adult subject. Stereoselective differences were observed in the plasma concentration versus time profiles of the enantiomers of both fenfluramine and norfenfluramine. The area under the plasma concentration versus time curve values obtained for the l-isomers of fenfluramine or norfenfluramine were higher than the values of their corresponding d-antipodes.

Pharmacokinetics of Fenfluramine and Neuroleptics in the Treatment of Refractory Schizophrenia

SummaryThis study was designed to investigate whether the addition of fenfluramine to neuroleptic therapy could produce an improvement in chronic schizophrenics who were limited responders to neuroleptics. Initially, each of 9 inpatients received at least 6 weeks’ treatment with placebo fenfluramine for baseline data collection. Thereafter, active fenfluramine therapy commenced at 60 mg/day with increments of 20 mg/day implemented every 2 weeks until a maximum daily dose of 120mg of fenfluramine was attained. This dosage level was maintained until fenfluramine was withdrawn by stepwise decrements, so that the duration of fenfluramine treatment did not exceed 12 weeks. The patients then continued to receive placebo fenfluramine for a minimum of 4 weeks for further evaluation and data collection. Throughout the study each patient was maintained on a constant dose of a neuroleptic drug.The stepwise addition of fenfluramine revealed significant correlations between dose and plasma concentrations for both isomers of fenfluramine and its pharmacologically active metabolite, nor-fenfluramine. Dose proportionality with the plasma concentrations of the isomers of parent and metabolite was also maintained during dose tapering. The plasma concentrations of the l-isomers of both fenfluramine and norfenfluramine were significantly higher than those of the corresponding d-isomers. Moreover, the l: d optical isomer ratios were constant at 1.9 for fenfluramine and 1.4 for norfenfluramine. Thus, it would appear that the enantioselective aspects of fenfluramine and its metabolite norfenfluramine were not affected by changes in the dose of fenfluramine. The presence of fenfluramine had no consistent effects on the steady-state plasma concentrations of either the neuroleptic drugs or metabolites.

The Interesting Case of Acyclovir Delivered Using Chitosan in Humans: Is it a Drug Issue or Formulation Issue?

ABSTRACTPurposeAttempts to formulate acyclovir to improve its bioavailability and reduce the frequency of dosing from the present q4h have not materialized.DiscussionIt was thought that an approach using permeability enhancer such as chitosan may impart improved absorption profile to acyclovir; however, the recently published pharmacokinetic data suggested otherwise. The lack of promise of chitosan formulation was attributed to the muco-adhesive properties of chitosan to hold off acyclovir and preventing its transport across the gastrointestinal tract. However, the above hypothesis was refuted by another published human pharmacokinetic study of fexofenadine formulated with chitosan formulation - in this work it was unambiguously shown that chitosan helped in enhanced absorption of fexofenadine which is a well-known Pgp substrate. If one examines the pharmacokinetic disposition of acyclovir, it is clear that renal elimination is so rapid necessitating frequent dosing of acyclovir. In summary, the ability of chitosan based formulations to aid in the oral absorption of drugs may be drug dependent as enumerated by data obtained from acyclovir and fexofenadine. While chitosan favourably improved the pharmacokinetics of fexofenadine, acyclovir may not be ideal for chitosan type of formulation.ConclusionThe choice of the drug and the formulation type intended to deliver the drug need to be made in a diligent and pragmatic fashion.