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The pivaloyloxyethyl ester of methyldopa is an antihypertensive prodrug possessing improved bioavailability properties over methyldopa. A sensitive cation-exchange, high-performance liquid chromatographic assay using electrochemical detection has been developed for the ester in plasma and urine in order to determine the extent of its hydrolysis after oral administration. The chromatographic conditions involve two Altex Partisil 10 SCX columns (25 cm X 4.6 mm) in series; a mobile phase consisting of methanol, potassium phosphate buffer, pH 3.0, and EDTA disodium dihydrate; and an electrochemical detector set at 0.5 V. The pivaloyloxyethyl ester in plasma or urine is extracted into ethyl acetate, back-extracted into 0.1 M sulfuric acid, and analyzed directly by high-performance liquid chromatography. For urine, the ethyl acetate extract is washed with a buffer (pH 8.0) prior to the back-extraction step. The assay gives a linear response over the concentration range of 10-160 ng/ml in plasma and 20-400 ng/ml in urine.

The (5-methyl-2-oxo-1,3- dioxol -4-yl)methyl and (5-tert-butyl-2-oxo-1, 3- dioxol -4-yl)methyl esters of 3-hydroxy-alpha-methyltyrosine (methyldopa) were prepared and evaluated as progenitors of the amino acid. 1H NMR experiments reveal that the esters are converted cleanly to methyldopa and the corresponding alpha-diketone at pH 7.4, with the 5-methyl derivative undergoing hydrolysis faster than the 5-tert-butyl analogue. Bioavailability studies in dogs show that the esters, particularly the 5-methyl derivative, yield significant plasma levels of methyldopa. Both esters are orally effective antihypertensive agents in spontaneously hypertensive (SH) rats. These studies indicate that (2-oxo-1,3- dioxol -4-yl)methyl esters are viable prodrugs for the latentiation of methyldopa.

Optically pure (+)-nicotine has been obtained from (+/-)-nicotine using a combination of d-tartaric acid and di-p-toluoyl-l-tartaric acid. As the di-d-tartrate salt, (+)-nicotine is less potent than (-)-nicotine di-l-tartrate in producing lethality in mice, on blood pressure in anesthetized rats, and in the isolated guinea-pig ileum, indicating substantial stereospecificity for nicotine receptors. Potency ratios are 0.14, 0.06, and 0.019, respectively.

Four subjects were studied by continuous intraduodenal sampling to establish the existence and determine the extent of enterohepatic recirculation of sulindac and its sulfide and sulfone metabolites. Sulindac, 200 mg by mouth, was given every 12 hr for 7 days. After the last dose was given intraduodenally, constant duodenal infusion of a nutrient mixture and sampling of duodenal contents were performed through a triple-lumen intraduodenal tube for 12 hr. Calculation of nonabsorbed drug in the samples and quantitation of drug and metabolite levels in the biliary secretions were made possible by nonabsorbable markers in the drug solution and in the infusate. Interindividual variations in the absolute values for each of the chemical species were over a 200% range, but for each subject relative clearances were in a remarkably constant ratio, averaging 1:12:12 for sulfide:sulindac:sulfone. Total biliary excretions of the prodrug (sulindac) and active pharmacophore (sulfide) calculated from these biliary clearances and historic mean plasma AUCs were 136% and 22% of dose. Thus, there is a correlation between data in man and those in five other species and the data established that, after sulindac, the contribution of enterohepatic circulation to conservation of the active pharmacophore is achieved predominantly at the level of inactive prodrug.

In a crossover study, the pivaloyloxyethyl ester (POE) of methyldopa, labeled either with 3H in the methyldopa moiety or 14C in the pivalic acid moiety, was administered orally to four volunteers in 1000-mg single doses (equivalent to 500 mg of methyldopa). The majority (93%) of either the 3H- or 14C-labeled dose was excreted in the urine. Methyldopa, which was assayed by a fluorometric technique, peaked (approximately 6 micrograms/ml) at 1 hr in the plasma. Forty-five per cent of the dose was excreted as methyldopa as opposed to 18% normally seen after oral methyldopa dosages. Intact POE was absent in the urine of three volunteers and present in only trace amounts in urine from a fourth volunteer. Thus, the oral dose of POE was well absorbed and rapidly hydrolyzed to methyldopa. After oral administration of methyldopa, methyldopa sulfate is the principal urinary metabolite in man. However, after administration of POE, a relatively small fraction (13%) of the dose was excreted as methyldopa sulfate. The major urinary metabolite of POE, other than methyldopa, was 3-OCH3 methyldopa. Methyldopamine was a minor metabolite. It was concluded that a shift from sulfation to methylation occurred in the metabolic profile of methyldopa when it was administered as POE and that the metabolites of POE (including conjugated pivalic acid) were rapidly eliminated from the body.

The preparation of 4, 4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole) from (+)-nicotine (Ib) via (-)-4, 4-dibromoco-tinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of la. However, distribution studies showed that the maximum brain levels of (-)-[3H]nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-μg/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.

A retrospective study of illicit phencyclidine (PCP), which consisted of 94 different cases or 213 individual samples, has shown that one third of both the powder/tablets and green plant material contained the synthetic contaminant 1-piperidinocyclohexanecarbonitrile (PCC). The mole % PCC/PCP ranged from 1 to 68%. The method of analysis was gas chromatography (3% OV-7, 205 degrees C) and in preparation for analysis the sample was dissolved directly in chloroform or extracted from a strongly acidic solution (0.1 N HCl). Using these extraction conditions PCC was found not to undergo measurable decomposition.

4,4-Ditritio-(-)-nicotine (5) of high specific activity (4.7 Ci/mmol) has been synthesized from (-)-nicotine via the readily prepared 4,4-dibromocotinine (3). Scatchard analysis of the binding of 5 to the crude mitochondrial fraction of whole rat brain revealed a Ka of 4.7 X 10(6) M-1 and 13 fmol of binding sites/mg of protein.

The biliary secretion of sulindac and metabolites after a single 400 mg oral dose of the drug was studied in 3 elective gallbladder surgical patients following placement of an occludable T-tube in the common bile duct. Bile and systemic plasma were sampled at frequent intervals for up to 36 h postdose. The apparent biliary clearance (Vcl,bile) of the prodrug sulindac is about 25 times greater than that of the pharmacologically active sulfide metabolite. The total biliary flux of drug in normal man with an uninterrupted enterohepatic cycle, calculated from Vcl,bile and historic mean plasma drug AUCinfinity0 values, averages 144 and 12.2 per cent of the dose as sulindac and the sulfide metabolite, respectively. Thus, enterohepatic recycling of the drug in man is principally in the form of the prodrug which not only limits exposure of the intestine to the active moiety but also sustains systemic concentrations of active drug upon reabsorption of the prodrug.

Optically pure (+)-nicotine has been obtained from (+/-)-nicotine using a combination of d-tartaric acid and di-p-toluoyl-l-tartaric acid. As the di-d-tartrate salt, (+)-nicotine is less potent than (-)-nicotine di-l-tartrate in producing lethality in mice, on blood pressure in anesthetized rats, and in the isolated guinea-pig ileum, indicating substantial stereospecificity for nicotine receptors. Potency ratios are 0.14, 0.06, and 0.019, respectively.

The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3 Ci/mmole)from (+)-nicotine (Ib) via (-) 4,4-dibromocotinine (IIIb) is described. Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in the CNS, its binding affinity for the crude mitochondrial or nuclear fraction of whole rat brain is only three times less than that of Ia. However, distribution studies showed that the maximum brain levels of (-)-[3H] nicotine are nearly twice those of (+)-[3H]-nicotine following administration of a 2-micrograms/kg dose. Binding affinity and disposition of the stereoisomers account for a portion of the pharmacological stereospecificity of nicotine.