Assessment of 19 years of a prospective national survey on drug-facilitated crimes in France.

Drug facilitated-crime or chemical submission (DFC/CS) is defined as the concealed or forced administration of psychoactive substances to a victim for criminal purposes. This is a national program set up in the early 2000 s in the form of a prospective multicenter survey, the results of which this manuscript presents. Over this 19-year period, 5487 cases were collected, analyzed and classified into 54 % of suspected cases, 29 % of chemical vulnerability (CV) cases and 17 % of proven DFC/CS cases. In the overall data, the most prevalent victims were female (81 %), with an average age of 27 years. Sexual assault was the most frequent aggression (77 %), followed by theft (14 %). Victims of proven DFC/CS cases were from of all ages including children and elderly. In 934 victims of DFC/CS, 100 various psychoactive substances were detected mostly represented by benzodiazepines and z-drugs (55 %), various sedatives including antihistamines (16 %) and non-therapeutic substances (16 %). Gamma-hydroxybutyric acid (GHB) was found in 4 % cases. In CV cases, alcohol (90 %) and cannabis (32 %) intake were mainly involved. In France, despite prevention messages, DFC/CS has been an epidemic for many years and has been proven by our national study. This national program has the aim to identifying the substances used but unfortunately not the goal to fight against this phenomenon. Since 2009, we observed a new modus operandi of the aggressors who pose as taxi drivers facilitating the reception of the victims leaving nightclubs. We can emphasize that GHB is not the "date rape drug" but rather the benzodiazepine class is.

Optimization of ICP-MS internal standardization for 26 elements by factorial design experiment.

INTRODUCTION: Internal standardization is a common tool used in inductively coupled plasma - mass spectrometry (ICP-MS) analysis in order to reduce matrix effects, and thus improve the reliability and the robustness of results. However, its efficacy relies on the choice of a proper internal standard (IS) which, ideally, undergoes the same signal variations as the analyte. Thus far, IS selection has mainly relied on the proximity of atomic mass between the analyte and the internal standard. However, while it may be a satisfactory rule of thumb, more recent works suggest that this criterium might not be suitable in several conditions, among which the presence of high amounts of carbon atoms in the sample. This may thus be of particular interest in the case of trace elements determination in biological samples. MATERIALS AND METHODS: In this study, we propose an empirical and global approach to IS selection in ICP-MS through the use of a factorial design of experiments (DoE), with a focus on biological matrices of interest in clinical analysis: human blood and urine. The suitability of 13 potential IS was evaluated for 26 clinically-relevant analytes, including a polyatomic ion obtained through reaction with oxygen, across 324 experimental conditions. RESULTS AND DISCUSSION: The results underline several exceptions to the rule of IS selection based on mass proximity, notably when considering heavy or polyatomic analytes. As a consequence, measurements of said analytes in several extreme experimental conditions using IS selected by mass proximity could yield vastly erroneous results (up to 30 times the theoretical concentrations). By contrast, the use of empirically selected IS yielded much more acceptable results.

Method validation and clinical application for the quantification of lopinavir, efavirenz, and ritonavir in breast milk using liquid chromatography tandem mass spectrometry.

A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been validated for quantification of three antiretroviral drugs (efavirenz [EFV], lopinavir [LPV], and ritonavir [RTV]) from human breast milk. The samples were extracted employing protein precipitation method using methanol as precipitating agent. The supernatant was evaporated and reconstituted before injecting into the chromatograph and separated on a biphenyl column. Calibration curves for the three tested antiretroviral drugs were linear (r ≥ 0.999) over the range examined. The inter- and intra-day coefficients of variation (CV) were ≤15% for efavirenz, lopinavir, and ritonavir. Mean recovery ranged from 96% to 105% and no major matrix effects were observed. This validated LC-MS/MS method was efficiently applied to determine EFV, LPV, and RTV concentrations in breast milk from Human Immunodeficiency Virus (HIV)-positive breastfeeding mothers. This assay requires a simple sample processing method with a short run time, making it well suited for high-throughput routine clinical or research purposes.

Urine toxicological screening method using an immunoenzymatic assay based on a biochip array technology: comparative study with immunochromatography and Liquid chromatography­mass spectrometry / Criblage toxicologique urinaire par une méthode automatisée immunoenzymatique multiparamétrique basée sur une technique de biopuce : comparaison à de l'immunochromatographie et de la chromatographie liquide couplée à de la spectrométrie de masse

Multiparametric toxicology research is mainly based on immunochromatography [IC] and chromatography methods. A new automated method using an immunoenzymatic (IE) assay based on a biochip array technology combines short turning around time and analytical performances close to chromatography in terms of positivity cut-off. The aim of our study was to compare IE versus IC and chromatography methods using urines samples from clinical cases. Seventy-two samples were analyzed by IC (amphetamines, opiates, benzodiazepines, THC, methadone, cocaine), IE and chromatography (previous classes plus opioids and cathinone). Immunochromatography results were read by at least 7 operators to assess reading subjectivity. Immunoenzymatic, IC, and chromatrography results were compared with each other. Chromatographic quantification was analyzed to understand discrepancies. Significant discrepancies (29-64%) were observed between IC and IE for most of the drug families investigated except for benzodiazepines, methadone and opiates. These discrepancies were not identified between IE and chromatography, except for some substances (28% to 67% discrepancies for buprenorphine, tramadol and oxycodone, 100% for cathinone). In contrast to IC, the performance of IE approached those of chromatography, except for some substances for which cross-reactions must be investigated. Reading discrepancies were frequent with IC (33% of samples) and made robust result output challenging. In conclusion, the Multistat® is an interesting method for first-line toxicological screening for laboratories without chromatography method.

La recherche des toxiques multiparamétrique repose principalement sur des méthodes immunochromatographie [IC] et de chromatographie (CL). Une nouvelle méthode automatisée immunoenzymatique (IE) (Multistat®) en biopuce, combine un rendu de résultats rapide et des performances analytiques, en termes de seuils de positivité, proche de la CL. L'objectif de notre étude a été de comparer l'IE à des méthodes d'IC et de CL sur des échantillons hospitaliers. Soixante-douze échantillons ont été analysés par IC (amphétamines, opiacés, benzodiazépines, THC, méthadone, cocaïne), IE et CL (classes précédentes plus opioïdes et dérivés de la cathinone). Les résultats d'IC étaient lus par au moins 7 personnes pour évaluer la subjectivité des lectures. Les résultats d'IE, d'IC et de CL étaient comparés entre eux. La quantification en CL était exploitée pour expliquer les discordances. Une forte proportion de discordances (de 29 à 64 %) était observée entre IC et IE sur la plupart des toxiques explorées sauf pour les benzodiazépines, la méthadone et les opiacés. Ces discordances n'étaient pas retrouvées entre IE et CL, hormis pour certaines substances (28 % à 67 % de divergences pour buprénorphine, tramadol et oxycodone, 100 % pour les dérivés de la cathinone). À l'inverse de l'IC, les performances de l'IE se rapprochaient de celles de la CL, sauf pour certaines substances pour lesquelles des réactions croisées doivent être recherchées. Les discordances de lecture étaient fréquentes en IC et rendent difficile un rendu de résultat robuste. En conclusion, le Multistat® est une méthode intéressante pour un criblage en première intention pour les laboratoires sans CL.

Evaluation of 4 quantification methods for monitoring 16 antibiotics and 1 beta-lactamase inhibitor in human serum by high-performance liquid chromatography with tandem mass spectrometry detection.

Antibiotic (ATB) prescription in an intensive care unit (ICU) requires continuous monitoring of serum dosages due to the patient's pathophysiological condition. Dosing adjustment is necessary to achieve effective targeted concentrations. Since ICUs routinely use a large number of ATBs, global monitoring needs to be developed. In the present study, we developed a global analytical method for extracting, separating and quantifying the most widely used ATBs in ICUs: amoxicillin, piperacillin, cefazolin, cefepime, cefotaxime, ceftazidime, ceftolozane, ceftriaxone, ertapenem, meropenem, ciprofloxacin, moxifloxacin, levofloxacin, daptomycin, dalbavancin, linezolid and a beta-lactamase inhibitor: tazobactam. To guarantee the robustness of the quantification, we differentiated the 16 ATBs and the beta lactamase inhibitor into 4 pools (ATB1 to ATB4), taking into account prescription frequency in the ICU, the physicochemical properties and the calibration ranges of the ATBs selected. The whole ATB was then separated with two LC columns in reversed phase: Kinetex Polar-C18 100 Å and Polar-RP-80 synergy, in less than 6.5 min. Detection was carried out by electrospray in positive ion mode, by tandem mass spectrometry (LC-MS/MS. The four quantification methods were validated according to the European guidelines on bioanalytical method validation (EMEA guide), after determining the extraction yields, matrix effects, recovery, precision, accuracy, within-run precision and between-run precision. For all analyses, bias is < 15% and is comparable to the literature and LOQs vary from 0.05 mg.L-1 for ciprofloxacin to 1.00 mg.L-1 for ceftriaxone and dalbavancin. The stability time of cefepime and piperacillin is 3 hrs and for the other ATBs 6 hrs in serum at room temperature. For long-term stability, freezing at - 80 °C guarantees 3 months of stability for ceftriaxone and dalbavancin and more than 6 months for the other ATBs.

Is there an interest for hair analysis in non-intentional pediatric cannabis intoxication?

BACKGROUND AND OBJECTIVES: The incorporation of drugs in the hair of young children differs from that of adults and the metabolism of cannabis cannot be the same. Our primary objective was to analyze the distribution of the different cannabinoids in children's hair samples. The secondary objective was to correlate the intensity of toxic environmental exposure to cannabinoid metabolite levels. METHODS: This was a prospective, single-center, observational pilot study of a pediatric cohort. Included subjects were all children less than 6 years of age admitted to a tertiary pediatric emergency unit for proven cannabis intoxication during the reference period. A hair strand was sampled within 12h of emergency admission. RESULTS: Forty-one pediatric patients were consecutively enrolled. Hair analysis showed that 34 children were positive for Δ9-THC (range 0.06-284.4ng/mg); 41 % of them were also positive for THC-COOH (range 0.26-2.76pg/mg). Depending on the Δ9-THC concentration (>1ng/mg), 39 % of the children could be considered exposed to an intensely toxic environment. The rate of THC-COOH detection steadily increased from 2015 to 2018 (18 %, 40 %, 50 %, 58 % for each consecutive year). Children intensely exposed weighed less on admission (p=0.02), had more comatose presentations (p=0.02), and more previous social issues (75 % versus 12 %, OR 22.0, p=0.0002). CONCLUSION: Hair testing in this context indirectly shows the intensity of children's toxic environmental exposure by the cannabinoid metabolite threshold. This was very helpful during the collegial examination of the toddlers' environment and led to a full investigation and to appropriate decisions concerning social measures.

Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases.

There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

Quinine unbound concentration is the best marker for therapeutic drug monitoring.

Quinine monitoring should be based on unbound concentration due to variable unbound fraction in malaria patients.

Medical and pharmacological approach to adjust the salbutamol anti-doping policy in athletes.

BACKGROUND: Salbutamol abuse detection by athletes is based on a urinary upper threshold defined by the World Anti-Doping Agency (WADA). However, this threshold was determined in healthy, untrained individuals and after a dose of salbutamol inhaled that might not really mirror the condition of asthmatic athletes and the experts's guidelines for asthma management. We aimed to revise this threshold in accordance with recommended clinical practice (that appear to be different from the actual WADA recommendation) and in exercise conditions. METHODS: For the present open-label design study, we included 12 trained male cyclists (20 to 40 y/o) with asthma. Differently from the previous pharmacokinetic study supporting the actual salbutamol urinary upper threshold, we decided to administer a close to recommended clinical practice daily dose of 3x200 µg.d(-1) inhaled salbutamol (instead of 1600 µg.d(-1) as authorized by the anti-doping policy). Urine salbutamol concentration was quantified by liquid chromatography-tandem ion trap mass spectrometry and corrected for urine density, at rest and after a 90-min cycling effort at 70-80 % of the maximal aerobic power. RESULTS: The maximum urine salbutamol concentration value peaked after the cycling effort and was 510 ng.mL(-1). That is twice lower than the actual WADA threshold to sanction salbutamol abuse, this "legal" threshold being based on pharmacokinetic data after a daily dose that is 8 fold the total dose sequentially administrated in our study. Considering its 95 % confidence interval, this threshold value could be more stringent. CONCLUSION: By using conditions in accordance with the experts' clinical and safety guidelines for asthma management in athletes undergoing an intense exercise bout, our study suggests that the urine salbutamol concentration threshold could be lowered to redefine the rule supporting the decision to sanction an athlete for salbutamol abuse.

[Tuberculosis: relevance of isoniazid dosage in prevention of liver side effects]. / Tuberculose: intérêt du dosage de l'isoniazide dans la prévention des effets hépatotoxiques.

OBJECTIVE: Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. METHODS: Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. RESULTS: The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. CONCLUSION: A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.

Does urine drug abuse screening help for managing patients? A systematic review.

BACKGROUND: In the field of addiction, assessment of psychoactive substance use is a key element. Nevertheless, self-reports and clinical examination underestimate the use of psychoactive substances. The implementation of urine drug screening tests (UDS) should improve this assessment. While the diagnostic value of UDS is well demonstrated, the consequences of carrying out UDS on medical management have not been established. Our aim was to summarize the evidence pertaining to the efficacy of UDS for medical management. METHODS: A systematic review of clinical trials, quasi-randomized and observational studies was performed using PubMed, Cochrane database of systematic review, Cochrane central register of controlled trials, PsycINFO, National Institute on Drug Abuse, ISI Web of Science. The methodological quality was assessed with the score developed by Starrels et al.; the report quality using the CONSORT and the STROBE checklists. The main outcome was medical management or consequences of management for patients in terms of psychoactive substance consumption and its complications, be they medical, social or professional. RESULTS: Eight studies met the inclusion criteria: one randomized clinical trial, two quasi-randomized studies, one cohort, and four cross-sectional studies. The methodological quality was judged to be poor, with the exception of the randomized clinical trial (fair quality). The value of UDS in managing patients was not clearly indicated in these studies. CONCLUSIONS: Few studies, with poor quality, have assessed the value of UDS in managing patients using psychoactive substances; though with insufficiency to demonstrate the interest of carrying out UDS. Therefore, pragmatic intervention studies are necessary.

Influence of pre-analytical conditions on plasma ribavirin concentrations.

Ribavirin (CAS 66510-90-5) associated to peginterferon (CAS 99210-65-8) is the current standard treatment for chronic hepatitis C. Exposure to ribavirin influences the virological response and anemia. Therefore monitoring plasma concentration of ribavirin is a useful tool for individualizing ribavirin dosing regimens. Ribavirin is a substrate of several nucleoside transporters that play a role in its distribution in erythrocytes. After blood sampling, it is essential to limit this mechanism. The aim of this study was to evaluate the influence of temperature and time on ribavirin plasma concentrations. Two blood samples, collected in EDTA tubes, were taken at the same time from 23 patients. One sample was conserved on ice whereas the second one was kept at room temperature during transport to the laboratory. Upon receipt at the laboratory and at different times post-reception (from 1 to 3 h), 1.5 mL of blood from each sample was centrifuged to obtain plasma that was then stored at -20 degrees C until assay. Samples were maintained in the same conditions as during transport for the 3 h. Plasma ribavirin was analysed using an HPLC-UV system. The results showed that mean loss of ribavirin concentration, for samples kept on ice as well as at room temperature, was less than 3%, 9% and 13% after 1, 2 and 3 h, respectively. These results suggest that blood samples for ribavirin analysis can be sent at room temperature within a period of 2 h between sampling and centrifugation.

Falsely elevated whole-blood tacrolimus concentrations in a kidney-transplant patient: potential hazards.

SUMMARY: Tacrolimus-based immunosuppression is the most frequently prescribed immunosuppression for kidney-transplant (KT) patients. Because tacrolimus has a narrow therapeutic window, drug monitoring is mandatory. Of the many methods used to assess whole-blood trough levels, antibody-conjugated magnetic immunoassay (ACMIA) is popular because, compared with microparticle enzyme-linked immunoassays (MEIA), there is no need to pretreat samples, thus reducing time taken by the laboratory technician. Herein, we report on a KT tacrolimus-treated patient who experienced falsely elevated whole-blood tacrolimus concentrations after using the ACMIA method. ACMIA gave trough levels of 24 ng/ml, whereas the actual trough level, when measured by enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography coupled with mass spectrometry (LC-MS/MS), was nil. After a workup we only found one factor that might have caused the elevated concentration: positive anti-double stranded DNA autoantibodies. We conclude that, when ACMIA produces surprisingly high tacrolimus concentrations in organ-transplant patients, these should be reassessed immediately using either LC-MS/MS or another immunoassay in order to eliminate falsely elevated results.

Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation.

Polyomavirus-associated nephropathy (PVAN) affects 1-10% of kidney-transplant (KT) patients, with graft failure/loss in approximately 90% of cases. Reducing immunosuppression is the key treatment option, but addition of leflunomide may improve BK Virus (BKV) clearance and graft survival. In a prospective open-labeled study, 12 KT patients with biopsy-proven PVAN were treated with reduced immunosuppression and leflunomide. BKV viremia and graft function were followed. PVAN was diagnosed at 6 months (3-192) post-transplant; median serum creatinine concentration (sCC) was 189 micromol/l (92-265). After 16 months (8-30) of follow-up, the sCC was 150 micromol/l (90-378, NS). Renal function improved in six cases (50%), remained stable in two (16.6%) and deteriorated in four (33.4%), with graft loss in two (17%). Clearance of BKV viremia was observed in five (42%) cases. Side effects included anemia in six cases leading to leflunomide withdrawal in two patients, and mild thrombocytopenia. In KT patients diagnosed with PVAN, leflunomide plus reduced immunosuppression improved graft function in 66.6%, cleared BKV viremia in 42%, and resulted in side effects in 17%. This limited efficacy contrasts with other reports and falls short of expectation. We conclude that active screening, earlier diagnosis and intervention remain the cornerstones of treatment.

A population pharmacokinetic approach to ceftazidime use in burn patients: influence of glomerular filtration, gender and mechanical ventilation.

AIMS: The aim of this study was to evaluate the disposition of ceftazidime in burn patients using a population pharmacokinetic approach, and to identify the clinical and biological parameters influencing its pharmacokinetics. METHODS: The development of the pharmacokinetic model was based on 237 serum ceftazidime concentrations from 50 burn patients. The determination of the pharmacokinetic parameters and the selection of covariates were performed using a nonlinear mixed-effect modelling method. RESULTS: A two-compartment model with first order elimination incorporating a proportional error model best fitted the data. Ceftazidime clearance (CL, l h(-1)) was significantly correlated with creatinine clearance (CL(CR)), and the distribution volume of the peripheral compartment (V2, l) was correlated with gender, mechanical ventilation and the CL(CR). The final model was defined by the following equations: Ceftazidime clearance was 6.1 and 5.7 l h(-1) for mechanically ventilated males and females, respectively, and 7.2 and 6.6 l h(-1) for nonventilated patients. The total volume of distribution was 31.6 and 49.4 l for mechanically ventilated males and females, respectively, and 22.8 and 28.1 l h (-1)for nonventilated patients. CONCLUSIONS: We have shown that gender, mechanical ventilation and CL(CR) significantly influence the disposition of ceftazidime in burn patients. Interindividual variability in the pharmacokinetics of ceftazidime was significant and emphasizes the need for therapeutic monitoring.

Intracellular and plasma efavirenz concentrations in HIV-infected patients switching from successful protease inhibitor-based highly active antiretroviral therapy (HAART) to efavirenz-based HAART (SUSTIPHAR Study).

OBJECTIVES: To assess intracellular and plasma efavirenz concentrations in HIV-infected patients who switched to efavirenz-based highly active antiretroviral therapy (HAART) from successful protease inhibitor-based HAART. PATIENTS AND METHODS: A total of 49 patients were included in this observational cohort study. At inclusion, all patients had plasma HIV-RNA levels<50 copies/mL and switched to efavirenz combined with two nucleoside reverse transcriptase inhibitors. Intracellular and plasma concentrations were measured 12 h post-dose, 1 month (M1) and 6 months (M6) after starting efavirenz. Virological success (VS) was defined as plasma HIV-RNA level<50 copies/mL within the first 12 months and remaining undetectable at the end of the follow-up. RESULTS: VS was documented in 48 patients for at least 12 months (range 12-78 months). High inter-patient variabilities of intracellular and plasma efavirenz concentrations were observed (coefficients of variation>40%). At M1 and M6, respectively, median [Q1; Q3] intracellular efavirenz concentrations were 5300 [2830; 11 530] and 6790 [3870; 8790] ng/mL, median plasma efavirenz concentrations were 2050 [1600; 3100] and 2100 [1410; 2500] ng/mL. No correlation was found between intracellular and plasma concentrations. Plasma efavirenz levels exceeded the proposed threshold of 1000 ng/mL in 96% of patients from M1. CONCLUSIONS: For moderately pre-treated HIV-infected patients with few mutations who switched to efavirenz from previous successful HAART, the proposed plasma efficacy-threshold was reached without any dosage adaptation. VS was maintained beyond 12 months, despite high inter-patient and intra-patient variabilities of intracellular and plasma efavirenz concentrations.

In vitro intestinal degradation and absorption of chondroitin sulfate, a glycosaminoglycan drug.

Chondroitin sulfate (CAS 24967-93-9, CS) is a natural polymer of a disaccharide consisting of glucuronic acid and N-acetyl glucosamine which is sulfated either in the 4 or 6 position. It is administered orally as a slow acting drug to treat osteoarthritis, though there is much debate about its effectiveness and its mode of action, given that macromolecules are not normally absorbed in the gastrointestinal (GI) tract. Initially using a spectrophotometric assay, the stability of CS was tested in the presence of both tissues and lumenal contents of stomach, small intestine, cecum and colon. There was no degradation by the contents of the stomach or small intestine or in any of the tissues. Degradation only took place in the contents of the colon and particularly the cecum. Using 14C-radiolabelled CS it was shown that the cecum contents degraded CS down to the component disaccharides. The 14C-radiolabelled CS was also used to investigate the transport of CS across the different parts of the GI tract in vitro. The CS was transported across the small intestine in low amounts in the intact form, probably by the mechanism of endocytosis. In the colon and the cecum, higher amounts of radioactivity were transported, but most of the radioactivity was in the form of the degradation products, the disaccharides. This study shows that small amounts of CS may cross the upper intestine intact, but in the distal GI tract the molecule is effectively degraded, presumably by the enzymes in the intestinal flora.

Influence of simulated weightlessness on the pharmacokinetics of acetaminophen administered by the oral route: a study in the rat.

During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible 'stress effect' caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow.