E. D. Korchinski

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.

Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol.

Single oral doses (5 mg) of haloperidol were administered to 36 healthy men (26 black, 10 white) of whom 28 (22 black, 6 white) completed the study. Plasma samples harvested over 96 hours were analyzed for haloperidol and reduced haloperidol by means of a new high performance liquid chromatographic method. Reduced haloperidol was detectable in the plasma of only six of the 28 subjects (five blacks, one white). In these individuals reduced haloperidol plasma concentrations were generally much lower than those of the parent drug. This finding in the present single-dose study is in contrast to literature reports that have described levels of reduced haloperidol higher than those of the parent drug in some patients chronically medicated with haloperidol. There was wide intersubject variation in area under the plasma concentration versus time curve and apparent oral clearance values for haloperidol. The distributions of these pharmacokinetic parameters about their respective means were each leptokurtotic and skewed toward higher values. In each case the geometric mean gave a better estimate of central tendency than the arithmetic mean. Wide intersubject variation prevented the detection of significant differences in these pharmacokinetic parameters between black and white subjects or between smokers and nonsmokers.

Pharmacokinetics of chlorpromazine and key metabolites

SummaryA study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (IV) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays.CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l·h−1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after IV CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ.After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4–38%) and dose dependant. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependant. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life. The mean AUC for the total conjugates of 7-HOCPZ was about two fold higher than that of the parent drug or any other metabolite. This shows that phase II metabolism plays a very significant role in the disposition of CPZ. As a result, the role of CYP2D6 in the 7-hydroxylation of CPZ cannot be fully assessed without taking phase II metabolism into account.

Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6

SummaryHaloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to determine if this reversible metabolic pathway is linked to the debrisoquine 4-hydroxylase isozyme of cytochrome P-450 (P450IID6), HAL (5 mg) or RHAL (5 mg) was orally administered to healthy male volunteers in a randomized crossover design both with and without a prior (1 h) oral dose of quinidine (250 mg bisulfate), a potent inhibitor of this isozyme. Thirteen volunteers, 11 extensive metabolizers, 2 poor metabolizers, completed all four phases of the study. Plasma samples harvested over seven days were analysed for HAL and RHAL. An expression for the apparent fractional availability of metabolite from the parent compound given (Fappinfmsupp) was derived and was used to determine whether HAL or RHAL is the preferred metabolite, and whether quinidine co-administration alters Fapp for either compound.The AUC (0-t) for both HAL and RHAL were significantly greater following the administration of either compound with quinidine compared with AUC (0-t) values obtained in the absence of quinidine. The maximum plasma concentration (Cmax) of the administered compound was also greater following the administration of quinidine. Quinidine had no effect on the half-lives of the administered compounds. The Fapp for HAL and RHAL were not significantly affected by the administration of quinidine, indicating that the interconversion of HAL and RHAL is not linked to P450IID6. The Fapp of RHAL after administration of HAL was significantly greater than the Fapp of HAL after RHAL administration, indicating that RHAL is the preferred metabolic form. This difference was not affected by quinidine.It is concluded that: 1) RHAL is the preferred form after administration of either compound and is not affected by quinidine, 2) the interconversion of HAL and RHAL is not affected by quinidine, indicating that this reversible metabolic process is not linked to P450IID6 and 3) there is a significant increase in the AUC (0-t) and Cmax values following quinidine co-administration with either HAL or RHAL. The precise mechanism of this interaction can not be established from this study, however, the observed increases in AUC (0-t) and Cmax may be explained with a simple tissue blinding displacement mechanism.

Metabolism of methoxyphenamine in extensive and poor metabolizers of debrisoquin

Urine and plasma concentrations of methoxyphenamine (MP) and three of its metabolites were determined after a single oral 60.3 mg dose of MP hydrochloride to healthy subjects of known debrisoquin (D) phenotype. Urine was collected from five extensive (EM) and five poor (PM) metabolizers of D for 12 hours and analyzed after treatment with β‐glucuronidase/sulfatase. There were marked interphenotype differences in the total urinary excretion of O‐demethylmethoxyphenamine (ODMP) and 5‐hydroxymethoxyphenamine (5HMP), as well as in MP/ODMP and MP/5HMP ratios. In contrast, the urinary output of N‐demethylmethoxyphenamine (NDMP) or MP/NDMP ratios showed no interphenotype differences. Plasma data from two EMs and two PMs showed that the mean values for maximum concentration, t½, and total AUC for MP were two‐, three‐, and sixfold greater, respectively, in PMs than in EMs. The plasma levels of ODMP and 5HMP were higher in EMs than in PMs, whereas the converse was true for NDMP. Thus, O‐demethylation and aromatic 5‐hydroxylation of MP are defective in PMs of D, resulting in increased MP and NDMP plasma levels. The form of cytochrome P‐450 involved in the N‐demethylation of MP is different from that responsible for O‐demethylation and aromatic 5‐hydroxylation.

N+-Glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans

1. Representative drugs of the various structural classes of H1 antihistamines were chosen for study. The drugs chosen (class name in parentheses) were chlorpheniramine maleate and pheniramine maleate (alkylamines), diphenhydramine hydrochloride and doxylamine succinate (ethanolamines), pyrilamine maleate and tripelennamine hydrochloride (ethylenediamines), promethazine hydrochloride (phenothiazine), cyclizine lactate (piperazine) and terfenadine (miscellaneous). In each case oral dose(s) were administered over no more than 6 h to two healthy volunteers and the total urine collected for 36 h. 2. Metabolites from urine were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of a synthetic authentic compound. 3. For eight of the nine drugs studied, metabolism by the N(+)-glucuronidation pathway was observed in each of the volunteers. Terfenadine was the exception. 4. The amount of each N(+)-glucuronide in the urine was estimated by h.p.l.c. analysis. The mean proportion of dose excreted as the metabolite was 14.3%, 6.5% and 4.0% for cyclizine, tripelennamine and diphenhydramine, respectively. Promethazine was the only case where the N(+)-glucuronide accounted for less than 1.0% of the administered dose in both volunteers examined.

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)

Interconversion between haloperidol and reduced haloperidol in healthy volunteers

SummaryThe interconversion between haloperidol (HAL) and reduced haloperidol (RHAL) was examined following their separate administration in low (5 mg) single oral doses to 15 young healthy male volunteers in a crossover design. Using an ultrasensitive HPLC method plasma concentrations of HAL and RHAL were monitored over a period of one week following each administration.Except in one case, both the analytes were found in the plasma of all the volunteers following each administration, thereby indicating interconversion of the two compounds. Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL.The disposition of HAL following administration of RHAL appears to be limited by its rate of formation and the disposition of RHAL following administration of HAL, on the other hand, is much slower than that of the parent compound.

Effects of food on the pharmacokinetics of methylphenidate.

AbstractPurpose. To test the hypothesis that the pharmacokinetics of d-meth- ylphenidate (d-MPH) would be altered by food ingested before administration of an immediate release formulation (dl-MPH- IR) but not when food is ingested before a slow release formulation (dl-MPH-SR). Methods. A randomized, four-phase, open label, crossover design was conducted in 24 healthy men who each received, on separate occasions, dl-MPH-IR and dl-MPH-SR taken after an overnight fast and 15 min after a standardized breakfast (20% protein, 21% fat, 59% carbohydrate). Plasma MPH levels were monitored by a validated, stereoselective, GLC-ECD method. Results. For plasma d-MPH, there were significant differences (ANOVA) between dl-MPH-IR and dl-MPH-SR in tmax, Cmax (peak exposure), and Cmax/AUC (sensitive to rate of absorption). Dl-MPH-SR on average delayed tmax from 2.3 to 3.7 h and lowered Cmax 34%. There was no significant difference between the formulations in AUC (extent of absorption). For dl-MPH-IR, food significantly increased Cmax (23%) and AUC (15%) and for dl-MPH-SR the corresponding increases were Cmax (17%) and AUC (14%). After dl-MPH-IR, food delayed average tmax from 2.0 to 2.5 but had no effect on tmax after dl-MPH-SR. There was no effect of food on Cmax/AUC (rate of absorption). Conclusions. Food caused a significant increase in extent of absorption but had no effect on rate of absorption of d-MPH after either dl-MPHIR or dl-MPH-SR.

Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase.

SummaryHealthy male volunteers (n=13) took a single oral dose of 60.3 mg of methoxyphenamine HCl with and without prior administration of either quinidine (250 mg as bisulphate salt) or its diastereomer quinine (300 mg as sulphate salt). Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in the 0–32 h urine.The oxidative routes of methoxyphenamine metabolism which had been previously shown to involve debrisoquine 4-hydroxylase, namely O-demethylation and 5-hydroxylation were both significantly inhibited by quinidine in the 12 extensive metabolizers. The inhibition was selective in that N-demethylation which does not involve this isozyme was not affected by quinidine. In all but one of these volunteers the methoxyphenamine/O-desmethylmethoxyphenamine ratio changed such that extensive metabolizers could be classified as poor metabolizers due to quinidine pretreatment. No marked change occurred in the renal excretion of methoxyphenamine and its three metabolites either in the extensive metabolizers because of quinine pretreatment or in the poor metabolizer because of treatment with either quinidine or quinine.Thus in the extensive metabolizer phenotype it was demonstrated in one study that enzyme inhibition of quinidine was selective in terms of the metabolic pathways inhibited as well as stereoselective with respect to the inhibitor.