Arthur B. Straughn

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol

PurposeTo examine the effect of common excipients such as sugars (sorbitol versus sucrose) on bioequivalence between pharmaceutical formulations, using ranitidine and metoprolol as model drugs.MethodsTwo single-dose, replicated, crossover studies were first conducted in healthy volunteers (Nu2009=u200920 each) to compare the effect of 5xa0Gm of sorbitol and sucrose on bioequivalence of 150xa0mg ranitidine or 50xa0mg metoprolol in aqueous solution, followed by a single-dose, nonreplicated, crossover study (Nu2009=u200924) to determine the threshold of sorbitol effect on bioequivalence of 150xa0mg ranitidine in solution.ResultsRanitidine Cmax and AUC(0–∞) were decreased by ∼50% and 45%, respectively, in the presence of sorbitol versus sucrose. Similarly, sorbitol reduced metoprolol Cmax by 23% but had no significant effect on AUC(0–∞). An appreciable subject-by-formulation interaction was found for ranitidine Cmax and AUC(0–∞), as well as metoprolol Cmax. Sorbitol decreased the systemic exposure of ranitidine in a dose-dependent manner and affected bioequivalence at a level of 1.25xa0Gm or greater.ConclusionsAs exemplified by sorbitol, some common excipients have unexpected effect on bioavailability/bioequivalence, depending on the pharmacokinetic characteristics of the drug, as well as the type and amount of the excipient present in the formulation. More research is warranted to examine other ‘common’ excipients that may have unintended influence on bioavailability/bioequivalence.

New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder

dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). The predominantly dopaminergic mechanism of the psychostimulant actions has become more clearly defined. Neuroimaging and genetic studies are revealing the underlying neuropathology in ADHD. Novel extended-release (ER) MPH formulations now offer drug delivery options to overcome both the short-term actions of immediate-release (IR) MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS® (Alza), Diffucaps® (Eurand) and SODAS™ (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH. The pharmacodynamics of the separate MPH enantiomers is in the process of further neuropharmacological characterisation. It is well established that dl-MPH undergoes marked stereoselective metabolism. Although l-MPH exhibits only minimal oral absorption, it may preferentially penetrate the brain, and interacts with ethanol to form the metabolite ethylphenidate. The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics. A long-acting formulation of d-MPH, which employs the SODAS technology, is in the advanced stages of clinical development.

Stability, Dose Uniformity, and Palatability of Three Counterterrorism Drugs—Human Subject and Electronic Tongue Studies

PurposeThese studies evaluated the ability of common household food and drink products to mask the bitter taste of three selected anti-terrorism drugs.MethodsThree anti-terrorism drugs (doxycycline, ciprofloxacin hydrochloride, and potassium iodide) were mixed with a variety of common household food and drinks, and healthy adult volunteers evaluated the resulting taste and aftertaste. In parallel, the ASTREE Electronic Tongue was used to evaluate taste combinations. Stability of the mixtures over time was monitored, as was the dosage uniformity across preparations.ResultsFoods and drinks were identified that satisfactorily masked the bitter flavor of each drug. Dose uniformity and stability were also acceptable over the range studied, although some combinations were significantly less stable than others. The electronic tongue was able to differentiate between tastes, but ranked masking agents in a different order than human volunteers.ConclusionsDoxycycline, potassium iodide, and ciprofloxacin, which are stockpiled in solid tablet form, can conveniently be prepared into more palatable formulations, using common household foods and drinks. The electronic tongue can be used to perform an initial screening for palatability.

Bioavailability of 11 phenytoin products

Eleven single lots of 100-mg phenytoin sodium capsules were evaluated for their relative bioavailability in 12 normal human volunteers. These products were manufactured by eight different companies and met all compendial specifications. The products were evaluated with respect to plasma levels at various times up to 96 hr following administration of single 100-mg doses, times of peak level, peak plasma concentrations, and areas under the plasma level—time curve. Several of the products exhibited statistically significant differences in the various parameters studied.

Bioavailability of microsize and ultramicrosize griseofulvin products in man

AbstractThe relative bioavailability of ten marketed dosage forms of griseofulvin was evaluated in two separate crossover studies. Each study utilized 12 healthy subjects, with eight of the subjects being common to both studies. Plasma griseofulvin concentrations were determined 1, 2, 3, 4, 6, 8, 10, 25, 34, 49, and 73 hr after dosing, using a high-pressure liquid chromatographic method. The “high-dose” study compared four microsize dosage forms administered as 500-mg doses and two ultramicrosize formulations given as 250-mg doses. The “low-dose” study employed four 250-mg microsize products and two 125-mg ultramicrosize products.nThe individual plasma level-time profiles for the majority of doses suggested prolonged absorption of microsize griseofulvin. The ultramicrosize dosage forms exhibited peak concentrations which were not significantly different (p>0.05) from those of the microsize products administered as twice the dose. In the high-dose study, the two 250-mg ultramicrosize dosage forms exhibited areas under the plasma level-time curve (AUC) which were significantly (p<0.05) less than the AUCs for all but one of the 500-mg microsize products. In the low-dose study the AUCs for the ultramicrosize products were significantly lower than the AUCs for all of the microsize dosage forms. Significant differences were also noted among the AUCs for the microsize products, although the maximum difference was less than 20% in both studies. A comparison of the AUCs observed in the high- and low-dose studies revealed that the AUCs for two of the 500-mg microsize dosage forms were only approximately 75% the AUC predicted from the 250-mg dose for the eight subjects common to both studies. All other formulations exhibited a dose proportionality for AUC.

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1–2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44–99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of “high,” “good,” “like,” “stimulated,” and overall “effect” were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)0-inf by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC0.5–2 hours was 2.1 times greater and the time to maximum concentration (Tmax) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.

Serious Bioavailability Problems with a Generic Prolonged‐Release Quinidine Gluconate Product

Abstract: A recently marketed prolonged‐release quinidine gluconate tablet was compared with the innovators tablet in a single‐dose bioavailability study with 12 healthy male subjects. The extent of absorption of quinidine from the new marketed product was only 50 per cent that of the innovators product. This finding, as well as projections of steady‐state plasma concentrations to be expected during multiple‐dose administration, indicated a bioequivalence problem with medically significant implications. The data obtained in this study resulted in a Class I recall of the less completely absorbed product by the U.S. Food and Drug Administration.

Determination of free disopyramide plasma concentrations using ultrafiltration and enzyme multiplied immunoassay.

Disopyramide is an antiarrhythmic drug that exhibits nonlinear binding to plasma proteins. As a result, the total body clearance increases with increasing total drug plasma concentration. A rapid and sensitive method for the determination of free (unbound) disopyramide plasma concentrations is described. The procedure employs an ultrafiltration system (Centrifree), which can be used for basic drugs, along with an enzyme multiplied immunoassay system (EMIT) for the measurement of free disopyramide concentrations in plasma water filtrate. The EMIT method was adapted to permit measurement of disopyramide in plasma over a concentration range of 0.02-1.2 micrograms/ml. Plasma storage at -20 degrees C, filtration volume, or the presence of buffer and mono-N-dealkylated metabolite in plasma did not affect the binding determinations. There was no loss of drug during the filtration process. A good correspondence was found between the EMIT assay and a high performance liquid chromatography method, when applied to plasma samples obtained from a human subject who had ingested disopyramide. Furthermore, the extent of protein binding determined by the ultrafiltration system and by equilibrium dialysis were in good agreement. The binding of disopyramide in fortified human plasma decreased from 64 to 52% over a total drug concentration range of 1-5 micrograms/ml.

The Influence of Dosage Form on Papaverine Bioavailability

The bioavailability of sustained-release papaverine HCl dosage forms were compared to equivalent doses of the drug administered as an elixir and conventional compressed tablets to 12 healthy human subjects. Papaverine plasma levels were determined using a gas-chromatographic procedure. The drug was absorbed more rapidly and completely from the two nonsustained-release formulations. There was a large intersubject variability, and the plasma half-life of the drug was esstimated to be 1 hour. The area under the plasma level-time curve for the nine sustained-release products ranged from 18 to 64% relative to the area achieved by the papaverine elixir. It was concluded that the sustained-release dosage forms of papaverine included in each study group could be considered bioequivalent, but they exhibited inadequate bioavailability relative to either the elixir or the compressed tablet dosage form.