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Two-phase derivatization with chloroformate esters of tertiary amines that contain a phenol group has been studied. The derivatives were analysed by gas chromatography with sensitive and selective detectors. The N,O-bis derivative of pentazocine was formed using an aqueous phase at pH 9.8, with tetrabutylammonium ion for extraction of the phenolate ion as an ion-pair. The organic phase comprised methylene chloride with trichloroethyl chloroformate or ethyl chloroformate. At pH 10.7 the derivative was hydrolysed by hydroxide ions extracted into the organic phase. Hydrolysis also occurred when more lipophilic counter-ions such as tetrapentyl-ammonium ions were used. Two-phase derivatization could also be achieved with toluene or ethyl acetate as the organic phase, although the reaction rate was considerably slower. The method was also applied to the assay of pentazocine in plasma. The best results were achieved after selective extraction of pentazocine from plasma, two-phase derivatization with ethyl chloroformate and determination by mass spectrometry or thermionic detection. The minimum detectable concentration of pentazocine was 10 ng/ml in a 1-ml plasma sample.

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20 survival patients were allowed to self-administer small intravenous doses of pethidine to relieve pain after major abdominal surgery. Pethidine injections were given by means of a programmable drug injector. Pethidine consumption varied from 12 to 50mg/h with a mean +/- SD of 26 +/- 10mg/h. The mean measured plasma concentration of pethidine during self-administration was 551 +/- 182 ng/ml, with a range of 132 to 896 ng/ml. Minimum effective concentrations averaged 455 +/- 174 ng/ml. Individual pethidine consumption and mean plasma concentrations did not differ between men and women, and were not correlated to variations in age, anthropometric factors, plasma clearance or elimination rate constant for pethidine. Individual consumption of pethidine was consistent, with stable plasma concentrations throughout most of the trial period. Pseudo-steady-state plasma concentrations of pethidine were established and maintained at widely different levels. 19 of the 20 patients obtained subjectively satisfactory analgesia.

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The influence of anaesthesia and surgery on the pharmacokinetics of pethidine (meperidine) was studied in 12 patients. Plasma pethidine concentrations in central venous blood collected during anaesthesia and the ensuing postoperative hours were by gas chromatography with electron capture detection. Postoperative analgesia was accomplished by patient-controlled intravenous administration of small doses of pethidine. The NONLIN program was used to calculate pharmacokinetic parameters for each individual. A single dose study of pethidine kinetics was carried out in all patients 3 to 5 days postoperatively. Mean +/- SD for peroperative Vd area was 4.3 +/- 1.7L/kg and for the elimination half-life was 6.1 +/- 3.6h. In the postoperative period Vdarea was 3.2 +/- 0.8L/kg and the elimination half-life was 3.2 +/- 1.4h. Plasma clearance increased from a peroperative value of 8.9 +/- 1.9 ml/min/kg to a postoperative value of 12 +/- 3.0 ml/min/kg. The changes in elimination half-life and plasma clearance are significant. The postoperative pharmacokinetics of pethidine were in accordance with those reported for healthy volunteers. The fraction of unbound pethidine was significantly reduced postoperatively - from 0.26 +/- 0.10 (peroperatively) to 0.18 +/- 0.10 (3 to 5 days later).

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Fifty-six surgical patients self-administered i.v. narcotic analgesics to combat postoperative pain. Analgesic demand per h was 2.7 +/- 1.1 mg of morphine, 26 +/- 10 mg of pethidine or 2.3 +/- 0.8 mg of ketobemidone, which reflects the equianalgesic ratios. Acute respiratory depression was seen in two hypovolaemic patients as evidenced by a raised PaCO2 on air breathing. Carbon dioxide retention disappeared upon correction of hypovolaemia. Late respiratory complications of short duration were encountered in 13%. Drowsiness and dry mouth were the most frequent complaints. Self-administered analgesia was considered highly satisfactory by the patients.

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The pharmacokinetics of pethidine has been studied in 12 patients subjected to major intraabdominal surgery. Pethidine and norpethine were analyzed in plasma samples collected during anesthesia and during patient-controlled administration of small intravenous doses of pethidine in the early postoperative period. A second study on the pharmacokinetics of pethidine was performed on the 3-5th postoperative day. The plasma clearance of pethidine was significantly lower in the preoperative study (8.9 +/- 1.8 ml x kg x min-1) compared with the postoperative study (12.0 +/- 3.1 ml x kg x min-1). Volume of distribution (Vd) was not significantly influenced, being 4.25 +/- 1.72 l x kg-1 peroperatively and 3.14 +/- 0.84 l x kg-1 postoperatively. Elimination half-life decreased from 5.91 +/- 3.57 h peroperatively to 3.25 +/- 1.40 h postoperatively. The kinetics of pethidine in the postoperative study agreed with pethidine kinetics reported for healthy volunteers. The fraction of unbound pethidine decreased from 0.26 +/- 0.1 peroperatively to 0.18 +/- 0.1 postoperatively. Norpethidine, a metabolite of pethidine, has been claimed to be responsible for several side effects like respiratory depression and convulsions during pethidine therapy. No side effect attributable to norpethidine was observed in the self-administration period. Norpethidine plasma concentrations did not exceed 500 ng/ml. The altered pethidine pharmacokinetics during anesthesia and the ensuing postoperative hours and the interindividual differences of the disposition of the drug strongly suggest that pethidine should be given by individualized regimens in surgical patients.

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Conditions for the extractive alkylation of eight sulphonylurea hypoglycemic drugs have been evaluated. Extractive methylation of the compounds was achieved within 90 min using tetrabutylammonium as counter-ion (0.1 M at pH = 6.9) with 5% methyl iodide in dichloro-methane as organic phase. Mass spectral analysis showed derivatives methylated at the sulphonamide nitrogen. A higher pH or use of tetrapentylammonium as counter-ion caused hydrolysis of the sulphonylureas. The derivatives showed a high electron-capture response with minimum concentrations detectable in the range 1-4 x 10(-16) moles sec-1. Therapeutic plasma concentrations of glipzide and tolbutamide were determined by direct extractive methylation of the compounds from the plasma sample. The glipizide derivative was determined by electron-capture gas chromatography down to about 20 ng/ml in a 0.5-ml plasma sample. The relative standard deviation at the 0.2 microgram/ml level of glipizide was 6% (n = 6). The corresponding figure in the determination of tolbutamide at the 10 microgram/ml level was 3% (n = 10).

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The extractive alkylation of 11 sulphonamide diuretics has been evaluated using tetrabutylammonium, tetrapentylammonium or tetrahexylammonium as counter ion at different pH values and methyl iodide in methylene chloride as the organic phase. The sulphonamides are methylated within 20 min with tetrahexylammonium as counter ion in 0.2 M sodium hydroxide at 50 degrees. The derivatives have been identified by mass spectral and nuclear magnetic resonance analysis. Relative retentions of the derivatives are given using 1% SE-30 as the stationary phase. A contaminant, dimethylsulphuric acid, occurs in methyl iodide and seriously disturbs the gas chromatographic analysis. The application of the extrative alkylation to biological samples is demonstrated by the direct analysis of acetazolamide in serum. 0.1 M tetrapentylammonium in 0.5 M sodium hydroxide is suitable as the aqueous phase with 1.6 M methyl iodide as alkylating reagent in methylene chloride. The trimethyl derivative of acetazolamide formed has been determined by electron-capture gas chromatography down to 0.5 microgram/ml in a 0.1-ml serum sample. The relative standard deviation at the 10 microgram/ml level is 6.6% (n = 10).

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The skin absorption of clioquinol and chloroquinaldol in ointment or cream base was studied in fourteen patients with widespread dermatoses. A serum concentration in the range of 0.3--1.3 microgram/ml using clioquinol and 0.05--0.1 microgram/ml with chloroquinaldol was reached by the second day and persisted throughout the topical treatment. The mean serum half-life of clioquinol and of chloroquinaldol was estimated to 25 and 6 hours, respectively. Local application of zinc oxide ointment after the end of the treatment chelate-bound the skin deposits of clioquinol and lowered the serum half-life to 11 hours. The mean daily urinary excretion of the applied amount of clioquinol and chloroquinaldol was 4.5 and 6%, respectively.

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The systemic absorption and the plasma concentrations of chloroquinaldol have been determined after local application of one vaginal tablet of Sterosan. A peak plasma concentration of 33 ng/ml was determined 12 h after application. A mean absorption of 6.0% of the applied dose was estimated.

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