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PubMed1989

[The plasma levels of haloperidol and reduced haloperidol in Japanese psychiatric patients].

We measured plasma levels of haloperidol (HAL) and its metabolite, reduced haloperidol (RHAL), in 30 psychiatric patients receiving haloperidol. HAL and RHAL levels were measured by reversed-phase high-performance liquid chromatography. The results were as follows. (1) Plasma levels of HAL had a highly positive correlation with daily dose per body weight (r = 0.902). (2) Distribution of individuals in relation to RHAL levels appeared to have a bimodal pattern. Of these 30 patients studied, 7 were identified as extensive metabolizers (23%). (3) RHAL/HAL ratios showed small intra-individual variance, while inter-individually they varied largely. The mean RHAL/HAL ratio in 30 patients was 0.692; when the 7 extensive metabolizers were excluded, it was 0.491. (4) In the individuals with clinical improvements, plasma levels of HAL and RHAL were 7.45 +/- 4.46, 3.96 +/- 2.16 ng/ml (mean +/- SD), respectively. Patients showing high plasma levels of HAL and RHAL (greater than 30 ng/ml) became aggravated during HAL treatment.

Adolescent↗
PubMed1988

Sensitive electrochemical high-performance liquid chromatography assay for the simultaneous determination of haloperidol and reduced haloperidol.

An electrochemical HPLC method for the simultaneous determination of haloperidol and reduced haloperidol in plasma is presented. Chlorohaloperidol serves as the internal standard. A cyanopropyl bond elut column was used for sample preparation. The eluate was evaporated and reconstituted with mobile phase and injected onto a nitrile bonded column. The chromatographic system consisted of an ESA Coulochem detector operated in the screen mode. Intra- and interassay coefficients of variation for both compounds were less than 7%, with a sensitivity limit of 20 pg on the column. A plasma level-time profile is presented to illustrate the sensitivity and applicability of this assay in small animal and human pharmacokinetic studies.

Animals↗
PubMed1992

Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair.

Profiles of the steady-state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4-30 mg/day, three times a day) for greater than 4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high-performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax, respectively) varied widely among patients: 3.0-22.9 and 6.2-32.7 ng/mL for HL and 2.8-21.4 and 5.7-33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration-time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 +/- 0.48, mean +/- standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax, or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.

Administration, Oral↗
PubMed1993

Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6.

Haloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to determine if this reversible metabolic pathway is linked to the debrisoquine 4-hydroxylase isozyme of cytochrome P-450 (P450IID6). HAL (5 mg) or RHAL (5 mg) was orally administered to healthy male volunteers in a randomized crossover design both with and without a prior (1 h) oral dose of quinidine (250 mg bisulfate), a potent inhibitor of this isozyme. Thirteen volunteers, 11 extensive metabolizers, 2 poor metabolizers, completed all four phases of the study. Plasma samples harvested over seven days were analysed for HAL and RHAL. An expression for the apparent fractional availability of metabolite from the parent compound given (Fapppm) was derived and was used to determine whether HAL or RHAL is the preferred metabolite, and whether quinidine co-administration alters Fapp for either compound. The AUC (0-t) for both HAL and RHAL were significantly greater following the administration of either compound with quinidine compared with AUC (0-t) values obtained in the absence of quinidine. The maximum plasma concentration (Cmax) of the administered compound was also greater following the administration of quinidine. Quinidine had no effect on the half-lives of the administered compounds. The Fapp for HAL and RHAL were not significantly affected by the administration of quinidine, indicating that the interconversion of HAL and RHAl is not linked to P450IID6. The Fapp of RHAL after administration of HAL was significantly greater than the Fapp of HAL after RHAL administration, indicating that RHAL is the preferred metabolic form. This difference was not affected by quinidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Interconversion between haloperidol and reduced haloperidol in healthy volunteers.

The interconversion between haloperidol (HAL) and reduced haloperidol (RHAL) was examined following their separate administration in low (5 mg) single oral doses to 15 young healthy male volunteers in a crossover design. Using an ultrasensitive HPLC method plasma concentrations of HAL and RHAL were monitored over a period of one week following each administration. Except in one case, both the analytes were found in the plasma of all the volunteers following each administration, thereby indicating interconversion of the two compounds. Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL. The disposition of HAL following administration of RHAL appears to be limited by its rate of formation and the disposition of RHAL following administration of HAL, on the other hand, is much slower than that of the parent compound.

Adult↗
PubMed1994

Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms.

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity-concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0.026) in plasma, and the blood:plasma ratio for each compound were independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The Vmax for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mumol/g protein per min (mean +/- SD), respectively. The Km was 110 +/- 40 and 70 +/- 10 microM, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 microM (the limit of HP solubility) in the same livers was 2.6 +/- 0.7 mumol/g protein per min. Despite the observed nonlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the Km for oxidation of each enantiomer of RHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Brain tyrosine depletion attenuates haloperidol-induced striatal dopamine release in vivo and augments haloperidol-induced catalepsy in the rat.

RATIONALE: There are conflicting reports as to whether alterations in tyrosine levels affect functional indices of striatal dopamine (DA) transmission. Since the DA antagonist haloperidol (HAL) increases striatal DA release and induces catalepsy through its actions on striatal DA systems, it provides a useful paradigm to assess both neurochemical and behavioral effects of lowering brain tyrosine levels. OBJECTIVES: To determine how brain tyrosine depletion affects HAL-induced catalepsy and striatal DA release in awake, freely moving rats. METHODS: In male rats, a control or tyrosine- and phenylalanine-free neutral amino acid solution NAA(-) (IP) was administered 30-60 min prior to HAL (IP). In one cohort, striatal microdialysate was assayed for DA levels. In a parallel cohort, catalepsy was measured using the bar test. RESULTS: NAA (-) reduced striatal tyrosine levels by 60%. The latter did not affect basal striatal DA release, but consistently delayed the attainment of maximal HAL-induced (0.19 mg/kg and 0.25 mg/kg SC) striatal DA release; the latter was abolished by administration of tyrosine. NAA(-) also potentiated HAL-induced catalepsy. CONCLUSIONS: Acute brain tyrosine depletion attenuates HAL-induced striatal DA release and potentiates haloperidol-induced catalepsy. Both effects can be reversed by administration of tyrosine. Overall, the data indicate that tyrosine depletion affects both neurochemical and behavioral indices of striatal DA release.

Animals↗
PubMed2006

Determination of haloperidol and reduced haloperidol in human serum by liquid chromatography after fluorescence labeling based on the Suzuki coupling reaction.

A simultaneous method for the determination of haloperidol (HP) and its metabolite, reduced haloperidol (RHP), in human serum was developed by means of high-performance liquid chromatography (HPLC) with fluorescence detection. Suzuki coupling reaction with a fluorescent arylboronic acid, 4-(4,5-diphenyl-1H-imidazol-2-yl)phenylboronic acid (DPA), was employed to convert HP and RHP into highly fluorescent compounds. HP and RHP were extracted from human serum by liquid-liquid extraction with a mixture of n-hexane and isoamyl alcohol (99:1, v/v) and subsequently labeled by reaction with DPA. Separation of DPA derivatives of HP and RHP was performed on a silica column with a mixture of acetonitrile and H(2)O (90:10, v/v) containing triethylamine and acetic acid as a mobile phase. The proposed method allowed sensitive detection of HP and RHP in human serum with a detection limit (at a signal to noise ratio of 3) of 0.22 and 0.20 ng/mL, respectively. The applicability of the method for therapeutic drug monitoring (TDM) was demonstrated by analyzing human serum samples from schizophrenic patients receiving HP.

Boron Compounds↗
PubMed1999

In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol.

OBJECTIVE: To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL). METHODS: The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied. RESULTS: After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes. CONCLUSION: The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence.

Biotransformation↗
PubMed1992

Splanchnic uptake of haloperidol and release of reduced haloperidol in vivo in the guinea pig.

Splanchnic uptake of haloperidol (HAL) and release of reduced haloperidol (RHAL) were studied in vivo in guinea pigs. Anesthetized animals with implanted cannulae in the aorta, the hepatic vein and the inferior vena cava were infused intravenously with HAL at a rate of 9.6 micrograms/min/animal for 90 min. Plasma HAL and RHAL in samples taken from the arterial and hepatic venous cannulae were measured by HPLC with an electrochemical detector. Contamination of the hepatic venous samples by blood from the inferior vena cava was ruled out by the validation method of tritiated water washout [Huang MT, J Appl Physiol 71: 359-364, 1991]. HAL concentrations plateaued at 70-80 ng/mL in the aorta and 5-7 ng/mL in the hepatic vein during the final 30 min of infusion. Splanchnic extraction of HAL was 91%. Hepatic blood flow was estimated to be 1.95 +/- 0.40 (SD) mL/min/g. If assuming that splanchnic uptake of HAL took place in the liver, a rate of uptake of HAL in the liver of 79.2 +/- 18.6 (SD) ng/min/g could be calculated by the Fick principle. The uptake in the whole liver accounted for 14% of the rate of HAL infusion into the animal. Plasma RHAL in the aorta, 6.4 +/- 6.6 (SD) ng/mL at 60 min and 9.4 +/- 4.6 (SD) ng/mL at the end of HAL infusion, was about 10-12-fold less than aortic HAL. The concentrations of RHAL in the hepatic vein were not significantly different from those in the aorta, indicating that splanchnic tissues including the liver are not responsible for plasma RHAL secretion. The highly efficient uptake of HAL as well as the ketone reductases found previously in vitro in liver microsomes of guinea pigs were probably involved only in biliary excretion of HAL.

Animals↗
PubMed1987

Reduced haloperidol and haloperidol: effects on homovanillic acid in caudate and prefrontal cortex.

The effects of acute administration of reduced haloperidol (RHAL) on homovanillic acid (HVA) in the caudate and prefrontal cortex were examined in rats. Haloperidol (HAL) was used as a reference compound. Concentrations of HVA and HAL were measured by HPLC/ECD. The maximal HVA response time was 3 hr after the injection, in both caudate and prefrontal cortex, for both RHAL and HAL. The potency of RHAL in the elevations of HVA in the caudate and prefrontal cortex was only about one-third to one-fifth that of HAL. The concentrations of HAL in the prefrontal cortex and caudate after RHAL administration were just about one-third to one-fifth those after HAL administration. These results suggest that less antidopaminergic activity of RHAL in this neuroleptic test might be explained by the lesser conversion of RHAL to HAL.

Animals↗
PubMed1991

Effects of ceruletide and haloperidol on the hypothalamo-pituitary beta-endorphin system and brain beta-endorphin contents in the rat: with special reference to effects of ceruletide in chronically haloperidol-treated rats.

Subcutaneous (sc) administration of 200 micrograms/kg ceruletide (CER), a decapeptide chemically related CCK-8, and 5 mg/kg haloperidol (HLP) to rats increased the plasma immunoreactive beta-endorphin (ir-beta-END) level. The combined injection of CER and haloperidol caused higher plasma ir-beta-END levels than either drug alone. High plasma ir-beta-END levels returned to control levels on the 2nd day. Prior intraperitoneal (ip) administration of a CCK receptor antagonist, L-364,718 (3 mg/kg), but not proglumide (400 mg/kg, ip), inhibited CER-induced, but not HLP-induced, elevation in plasma ir-beta-END levels. The dopamine agonist, bromocriptine (1 mg/kg, ip) decreased plasma ir-beta-END levels, but had not effect on CER-induced elevation in plasma ir-beta-END levels, whereas bromocriptine-induced reduction in plasma ir-beta-END levels was antagonised by HLP. CER injection to chronically HLP-treated rats caused a greater elevation of plasma ir-beta-END levels compared to saline-injected rats. In contrast to the acute experiment, plasma ir-beta-END levels remained elevated over a period of 24 h. In the acute experiment, CER, HLP or the combined treatment with these two drugs had no effect on ir-beta-END contents in the pituitary gland and brain. In the chronic experiment, HLP increased the adenohypophyseal and septal ir-beta-END contents and decreased the hippocampal ir-beta-END contents 24 h after the final HLP injection. CER caused a small reduction only in the hippocampal ir-beta-END contents of CER-injected rats 15 min after injection. When determined on the 2nd day, however, the increases in the adenohypophyseal and septal ir-beta-END contents and the decrease in the hippocampal ir-beta-END contents observed in CER-injected rats were of the same magnitude as those of rats not given the CER injection. These findings indicate that CER stimulates the release of ir-beta-END from the adenohypophysis through CCK-A receptors and that elevated plasma ir-beta-END levels is partly involved in some behavioural effects induced by CER. Furthermore, sustained elevation of plasma ir-beta-END levels after a single injection of CER to chronically HLP-treated rats may explain its long-lasting therapeutic and behavioural effects.

Animals↗
PubMed1990

Hypothalamic lesioned rats given haloperidol mimic the behavior of intact rats given haloperidol plus morphine.

Lateral hypothalamic (LH) damage produces rats which exhibit sensory neglect, somnolence and akinesia, while ventromedial hypothalamic (VMH) damage produces rats which exhibit sensory hyperesponsiveness (Marshall and Teitelbaum, 1977). Rats with large lesions of both LH and VMH are somnolent and akinetic but hyperesponsive to touch. When given haloperidol (5 mg/kg) the LH-VMH-damaged rats adopt an actively maintained splayed out posture, in which the limbs are abducted and extended and the body lies flat on the ground. While in this posture, reflexes of postural stability, such as buttressing against a displacing force, are partially inhibited. These postural characteristics are similar to those of normal rats given haloperidol (5 mg/kg) plus morphine (20 mg/kg) (Pellis et al., 1986).

Animals↗
PubMed1995

Pharmacoclinical correlations in schizophrenic patients treated with haloperidol decanoate: clinical evaluations, concentrations of plasma and red blood cell haloperidol and its reduced metabolite, and plasma homovanillic acid.

1. The aim of this open study was to determine whether a more rational therapeutic approach could be devised for psychotic patients (n = 11) treated for long periods with long-acting (LA) haloperidol. The mean multiplication factor for the transition from the oral formulation to the long-acting one was 12.8 (10.4, standard deviation), lower than the theoretically recommended factor of 20. 2. The best dose (mg/kg)-concentration correlations were found for haloperidol (HAL) and reduced HAL (RHAL) in the red blood cells (RBC) (representative of the free drug fraction) rather than in the plasma of patients that had attained the steady state (at the third cycle and afterwards) 3. Pharmacokinetic analyses were conducted at the same time as clinical evaluations, grading using the BPRS and determinations of plasma levels of total, free and conjugated homovanillic acid (HVA), a marker of central dopaminergic activity. 4. A between groups comparison at the steady state (patients (n = 20) with oral administration and the above patients (n = 11) with long-acting form of HAL), showed that the plasma and RBC RHAL/HAL ratios of long-acting HAL decreased significantly (p < 0,005) in comparison with oral administration, at least by half. 5. Plasma HVA values complete the information provided by plasma and more especially RBC HAL and RHAL levels. All these results taken together, as substantiated by the clinical assessment scales (BPRS), assure a better pharmacoclinical surveillance and can be predictive of a patient's response.

Adult↗
PubMed1997

Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.

1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.

Adolescent↗
PubMed1989

An improved sensitive assay for simultaneous determination of plasma haloperidol and reduced haloperidol levels by liquid chromatography using a coulometric detector.

A simple, highly sensitive and specific high-performance liquid chromatographic method that uses a coulometric detector for the simultaneous assay of haloperidol and reduced haloperidol in human plasma has been developed, using bromoperidol as the internal standard. A reversed phase C8 5-microns column (25 x 0.46 cm) and a mobile phase of phosphate buffer (pH 7.0), acetonitrile, and methanol (40:20:40 vol/vol) are used for separating the analytes. The analytes are extracted from alkalinized plasma using a mixture of pentane and isopropanol (95:5 vol/vol) and purified by back extraction into a perchloric acid solution. Teflon tubes with screw caps are used throughout the extraction work. The compounds are oxidized at a potential of +0.90 V against a Ag/AgCl reference electrode. The detection limit of the assay is 50 ng/L using 1 mL of plasma. The average interassay coefficient of variation for samples of concentration 1-40 micrograms/L is approximately 8%. Possible drug interferences in the assay have been studied. The absolute recovery of the method is approximately 80%. The assay has been validated by quantitating 150 schizophrenic patients' samples.

Chromatography, High Pressure Liquid↗
PubMed1998

Comparison of two high-performance liquid chromatographic methods for monitoring plasma concentrations of haloperidol and reduced haloperidol.

Two high-performance liquid chromatographic methods for monitoring haloperidol (HAL) and reduced haloperidol (RHAL) plasma concentrations were compared. In one method ultraviolet detection and a C18 column were used (UV method); in the other method electrochemical detection and a CN-column were used (EC method). Both methods are accurate and precise. For plasma samples spiked with HAL or RHAL, an excellent correlation was observed between the concentrations of HAL and RHAL found with both methods (r < or = 0.99, p < 0.01). However, for plasma obtained from patients treated with HAL the correlation between the two methods was poor (r > or = 0.71, p < 0.01). The main reason for the discrepancy between the two methods is probably interference of comedications or their metabolites, mostly in the EC method. Although the quantitation limit of the UV method (2 ng/ml for HAL and RHAL) is higher than that of the EC method (0.5 ng/ml for HAL and RHAL), the UV method is to be preferred for monitoring plasma levels in psychiatric patients because there is less interference from comedication.

Administration, Oral↗
PubMed1999

Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients.

The effects of smoking, CYP2D6 genotype, and concomitant use of enzyme inducers or inhibitors on the steady state plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were evaluated in 92 schizophrenic inpatients. All but three of these patients received concomitant medication, in many cases with drugs potentially interacting with HAL. Of the 92 patients, 63 were treated orally with HAL in a daily dose of 0.4 to 50 mg; 29 patients were treated intramuscularly with a daily equivalent dose of HAL decanoate (expressed as HAL) of 1.8 to 17.9 mg. A wide interindividual variation in HAL dose and in steady state plasma concentrations of HAL and RHAL was observed. In the patients treated orally, the daily oral dose was about 4 times higher and the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers (n = 40) than in nonsmokers (n = 23) (p < 0.01). The dose-normalized RHAL (but not HAL) plasma concentrations and the RHAL/HAL ratio were significantly higher in poor metabolizers (PMs) than in extensive metabolizers (EMs). There was a trend toward an effect of potentially interacting drugs (inducers or inhibitors) on dose, dose-normalized HAL and RHAL plasma concentrations, and the RHAL/HAL ratio. In the patients treated intramuscularly, the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers than in nonsmokers, but no differences in doses were observed. This naturalistic study of modest sample size in a polymedicated population shows an effect of smoking and CYP2D6 genotype (and to a lesser extent, of interacting drugs) on the kinetics of HAL.

Adult↗