Determination of allicin, S-allylcysteine and volatile metabolites of garlic in breath, plasma or simulated gastric fluids.

Various components of garlic and aged garlic extract, including allicin, S-allylcysteine (SAC) and volatile metabolites of allicin were determined in breath, plasma and simulated gastric fluids by HPLC, gas chromatography (GC) or HPLC- and GC-mass spectrometry (MS). Data indicate that allicin decomposes in stomach acid to release allyl sulfides, disulfides and other volatiles that are postulated to be metabolized by glutathione and/or S-adenosylmethionine to form allyl methyl sulfide. SAC can be absorbed by the body and can be determined in plasma by HPLC or HPLC-MS using atmospheric pressure chemical ionization (APCI)-MS.

The determination of metabolites of garlic preparations in breath and human plasma.

Gas Chromatography-Mass Spectrometry (GC-MS) was the major technique used to determine various metabolites after consumption of dehydrated granular garlic and an enteric-coated garlic preparation, in breath, plasma, and simulated gastric fluids. A special short-path thermal desorption device was used as an introduction technique for the gas chromatograph for the determination of volatiles. These garlic preparations release allicin, which decomposes in stomach acid or with time in the intestine to release allyl sulfides, disulfides and other volatiles, some of which are postulated to be metabolized by glutathione and/or S-adenosylmethionine to form allyl methyl sulfide, the main sulfur containing volatile metabolite. S-Allylcysteine, a non-volatile bioactive component of aged garlic preparations, was determined in human plasma and urine by HPLC-MS using the negative ion atmospheric pressure chemical ionization mode (APcI)- MS. The technique of selected ion monitoring was used for quantitation. A synthetic internal standard of deuterated S-allylcysteine was added to the plasma or urine to ensure recovery and to obtain reliable quantitative data.

Quantitation of the enantiomers of rimantadine and its hydroxylated metabolites in human plasma by gas chromatography/mass spectrometry.

A gas chromatographic/mass spectrometric procedure has been developed for the quantitation in human plasma of the enantiomers of rimantadine and its three hydroxylated metabolites. The assay utilized derivatization of all analytes with the optically active reagent S-alpha-methyl-alpha-methoxy(pentafluorophenyl)acetic acid, selective ion monitoring, methane negative ion chemical ionization mass spectrometry and stable isotope dilution techniques. This method has been used to measure plasma concentrations of the enantiomers of rimantadine, m-hydroxyrimantadine and p-hydroxyrimantadine (equatorial and axial epimers) in the ranges 2.5-250, 2.5-50, 1.25-62.5 and 1.25-62.5 ng/mL, respectively, in six subjects given a single 200 mg dose of racemic rimantadine. Although there are no significant differences in the concentration-time profiles of R- and S-rimantadine, large stereospecific differences in the disposition of their metabolites are observed.

The pharmacokinetics of midazolam in patients with congestive heart failure.

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age- and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.

A pilot study of the bioavailability and pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS or AIDS-related complex.

Eight patients with AIDS or ARC received four single doses of 2',3'-dideoxycytidine (ddC). The treatments included 0.5 and 5 mg oral tablets, a 0.5 mg oral solution, and a 0.5 mg intravenous infusion. Blood samples were collected for 4 to 6 h after each dose. Plasma concentrations of ddC were determined by a specific gas chromatographic-mass spectrometric (GC-MS) assay. A combination of the low dose and the assay sensitivity of 2 ng/ml limited data treatment and comparison. Mean Cmax of 8.5, 7.6, and 79.0 ng/ml occurred at mean tmax of 1.1, 1.3, and 0.9 h for the 0.5 mg oral solution, the 0.5 mg tablet, and the 5 mg tablet, respectively. A mean clearance of 5.57 ml/min/kg and volume of distribution of 0.64 L/kg were determined from the 0.5 mg intravenous infusion. Half-life values ranged between 0.95 and 2.0 h and appeared to be independent of the dose and route of administration. The bioavailability values calculated for the oral tablets were variable, ranging from 54 to 127%. Single doses of ddC were well tolerated in this population. The results of this pilot study indicate that ddC is rapidly and extensively absorbed when administered as an oral tablet or solution to fasting AIDS or ARC patients. It is also rapidly eliminated with a half-life of 1-2 h. There are no apparent differences in the absorption or elimination of ddC between 0.5 and 5 mg oral doses.

Determination of rimantadine and its hydroxylated metabolites in human plasma and urine.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation of the antiviral agent rimantadine and its meta- and para-hydroxylated metabolites in human plasma and urine. The assay utilizes an extractive pentafluorobenzoylation at alkaline pH with cyclohexane saturated with triethanolamine-chloroform (2:1) containing pentafluorobenzoyl chloride, selective ion monitoring, methane negative ion chemical ionization mass spectrometry and stable isotope dilution. The method has been used to measure plasma concentrations of rimantadine, m-hydroxyrimantadine and the two epimers of p-hydroxyrimantadine between 5-250, 5-100 and 2.5-50 ng/ml, respectively. Similarly, the urine concentrations of these analytes measured were between 25-1250, 25-500 and 12.5-250 ng/ml, respectively.

Quantitative determination of naltiazem in human plasma by gas chromatography/mass spectrometry.

A gas chromatographic/mass spectrometric procedure has been developed for the quantification of a diltiazem analog, naltiazem, in human plasma. The assay utilizes an extraction at neutral pH with hexane:ethylene dichloride:methyl-t-butyl ether (70:20:10), selective ion monitoring, methane or ammonia positive chemical ionization mass spectrometry and stable isotope dilution. The method has been used to analyze plasma concentrations of naltiazem in clinical samples over a range of 2-200 ng ml-1, using 1 ml of plasma.

Quantitation of the benzodiazepine antagonist flumazenil in human plasma by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation of the benzodiazepine antagonist flumazenil in human plasma. The assay utilizes an extraction at alkaline pH with benzene-dichloroethane (80:20), selective ion monitoring, isobutane positive-ion chemical ionization mass spectrometry and stable isotope dilution. The method has been used to measure plasma concentrations of flumazenil in over 1500 clinical samples over a range of 0.5-200 ng/ml (using 2 ml of plasma).

Quantification of dideoxycytidine in human plasma by gas chromatography/mass spectrometry.

A gas chromatographic/mass spectrometric procedure has been developed for the quantification in plasma of dideoxycytidine (DDC), a candidate anti-AIDS drug. The assay uses an extraction with ethyl acetate containing 10% methanol followed by three derivatization steps: (i) reaction with t-butyl dimethyl chlorosilane to silylate the 5'-hydroxyl group; (ii) pentafluorobenzoylation of the amino group with pentafluorobenzoyl chloride; (iii) methylation of the ring nitrogen adjacent to the amino group with diazomethane. The resulting derivative is quantified using stable isotope dilution, selective ion monitoring and methane negative chemical ionization mass spectrometry. Plasma concentrations of DDC were measured over a range of 2-200 ng ml-1 using 1 ml plasma for extraction.

Quantitation of the enantiomers of rimantadine in human plasma and urine by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation in plasma and urine of the enantiomers of rimantadine, an antiviral drug effective against type A influenza. The assay utilizes derivatization with an optically active reagent, selective ion monitoring, methane negative-ion chemical ionization (NICI) mass spectrometry and stable isotope dilution. The method has been used to measure concentrations of each rimantadine enantiomer over a range of 2.5-250 and 12.5-1250 ng/ml in the plasma and urine, respectively, of four male volunteers administered rimantadine. In plasma and urine, no differences were observed in the disposition of the unconjugated enantiomers. In urine, one enantiomer, but not both, was released following enzymatic hydrolysis.

Quantitative determination of rimantadine in human plasma and urine by GC-MS.

A GC-MS procedure has been developed for the quantitation in plasma and urine of rimantadine, an antiviral drug effective against type A influenza. The assay utilizes selective ion monitoring, methane negative ion chemical ionization (NCI) and stable isotope dilution. Sensitivity to NCI is effected by derivation of rimantadine with pentafluorobenzoyl chloride. The method has been used to quantitate plasma concentrations of rimantadine over a range from 4.2 ng/ml to 416 ng/ml, and urinary concentrations of rimantadine over a range of 21 ng/ml to 2077 ng/ml.