Ethyl glucuronide (EG) is a useful marker of alcohol consumption because its presence in urine can be detected up to five days. We investigated the impact of diuresis on the urinary excretion of EG, a minor ethanol metabolite. Seven healthy volunteers drank 250 mL of wine (25 g ethanol) in 15 min and, 240 min later, ingested 1 L of water within 15 min. Urine was voided before the drinking started and every 30-60 min for 400-550 min thereafter. Urinary ethyl glucuronide (UEG), creatinine, and ethanol were determined using liquid chromatography-tandem mass spectrometry, Jaffé's method, and the enzymatic ADH method, respectively. The maximum diuresis coincided with the lowest values of the UEG concentrations of 2 mg/L and the lowest creatinine values of 10 mg/dL 250-400 min after drinking. After drinking the wine, the urinary creatinine decreased slowly. After a short period of increasing, it decreased to minimum values caused by the water intake. After the intake of 1 L water, the diuresis increased within 60 min to its maximum. The amount of ethyl glucuronide excreted in urine was 10 mg (SD 5 mg) corresponding to 0.04% (SD 0.02%) of the dose administered. In successive voids during the elimination phase, the UEG and the diuresis were influenced after the subjects drank 1 L of water. Minimum UEG values of 0.5 mg/L could still be measured. Measuring UEG provides a reliable way to monitor recent drinking of alcohol. However, urinary creatinine needs to be measured additionally. Establishing a cutoff value of 25 mg/dL for urinary creatinine in diluted samples, like for the analysis of illicit drugs, is recommended. If the creatinine value is too low, the analyst has to decide about the further procedure.

The distribution of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in whole blood, plasma, and packed erythrocytes was studied. Parameters investigated were the hematocrit values (10, 42, 44, and 71%) and the water content of the samples. The blood-to-plasma ratio of morphine concentrations was unaffected by variations in hematocrit and water content, whereas the corresponding ratios for M3G and M6G were strongly influenced. Ratios were 0.53 to 0.65 and 0.52 to 0.62 in specimens with average hematocrit values (42 and 44%, respectively), and the ratios were 0.81 or 0.89 (hematocrit 10%) and 0.27 or 0.28 (hematocrit 71%) in blood samples with different hematocrit values. In contrast to the morphine conjugates, morphine was highly bound to or partitioned into red blood cells (beta e = 55.9). Although the present data are limited, they already demonstrate that conclusions drawn from pharmacokinetic studies and transferred to parent drug to metabolite ratios resulting from forensic blood samples may be biased by the particular biological matrix under investigation.

The disposition of heroin and its metabolites was investigated in four healthy male volunteers following intranasal administration of 6 and 12 mg heroin hydrochloride. In addition, two doses of 6 mg heroin hydrochloride were injected intramuscularly for comparison of pharmacokinetic parameters. Serum samples were analyzed for heroin, 6-acetylmorphine, and morphine by solid-phase extraction-gas chromatography-mass spectrometry. The concentration of morphine glucuronides was determined by high-performance liquid chromatography based on the native fluorescence of the conjugates. Major findings were rapidly rising and declining terminal phases for heroin and 6-acetylmorphine and slowly declining phases of morphine and metabolites after both routes of administration. The area under the curve values of morphine-3-glucuronide depended on dose but not on route of administration. The apparent terminal half-lives of morphine-3-glucuronide ranged from 2.2 to 5.2 h for intranasally administered heroin and were 3.0 and 1.7 h for the intramuscularly applied drug. A mean morphine-3-glucuronide-heroin area-under-curve ratio of 93 for the intranasal route as compared with 38 for the intramuscular route demonstrated that circulating amounts of heroin were about half the size after intranasal administration of the same dose.

The postmortem distribution of morphine and its metabolites was investigated in four cases of heroin overdose to evaluate some of the factors that influence intravasal blood concentrations. Variables included were the chemical stability of morphine conjugates, hemoconcentration, incomplete distribution of the drug and diffusion processes. Blood samples from different sampling sites including the aorta, the infra- and suprarenal portion of the inferior vena cava, the superior vena cava, the femoral and subclavian veins, and the right and left ventricles were examined for morphine, morphine-3-glucuronide and morphine-6-glucuronide, hematocrit and water content. Drug concentrations were determined by HPLC based on the native fluorescence of the analytes. Morphine glucuronides proved to be stable for a time period of 72 h. The water content ranged from 65 to 83% and hematocrit values from 25 to 75%, and were seen as contributory factors to the dramatic differences observed for drug concentrations from different sampling sites. The differences could neither be attributed to incomplete distribution during life-time nor to a diffusion process following the different distribution volumes of morphine and its conjugates. A definite relationship between the ratio of the molar concentrations of morphine and its glucuronides, as assessed in pharmacokinetical studies after morphine dosing, could not be established. For a better understanding more cases and changes over time and tissue concentrations should be analysed.

BackgroundThe antidiarrheal drug loperamide is frequently used to treat ritonavir‐associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood‐brain barrier, both of which might be altered by ritonavir, a potent P‐glycoprotein and cytochrome P4503A inhibitor.MethodsA 16‐mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo. Detailed pharmacokinetics of loperamide and its metabolites were determined over 72 hours. Central opioid effects were measured by evaluation of pupil diameter, cold pressor test, and transcutaneous PCO2 and PO2.ResultsRitonavir caused a major pharmacokinetic interaction, increasing the area under the concentration‐time curve of loperamide from 104 ± 60 h · pmol/ml after placebo to 276 ± 68 h · pmol/ml and delayed formation of the major metabolite desmethylloperamide (time to reach maximum concentration after drug administration [tmax], 7.1 ± 2.6 hours versus 19.6 ± 9.1 hours). The urinary metabolic ratio of loperamide increased 3 times whereas the total molar amount of loperamide and metabolites excreted in urine remained unchanged. No central pharmacodynamic effects were observed after coadministration of loperamide with either ritonavir or placebo.ConclusionThis study demonstrates a major metabolic interaction probably by cytochrome P4503A4 with no evidence of P‐glycoprotein involvement. This might explain the lack of central effects after ritonavir.Clinical Pharmacology & Therapeutics (2001) 70, 405–414; doi: 10.1016/S0009‐9236(01)35864‐2