Drug Concentration Monitoring Research Articles

Liquid chromatographic method for the determination of ganciclovir and/or acyclovir in human plasma using pulsed amperometric detection

We have developed a simple, rapid and highly sensitive method for determining plasma concentrations of ganciclovir and/or acyclovir by using reversed-phase chromatography followed by pulsed amperometric detection. A linear relationship between the amount of ganciclovir (0.05–10 μg/ml plasma) or acyclovir (0.1–20 μg/ml plasma) and peak height ratio was obtained. The relative standard deviations of all standard curves were greater than or equal to 0.999. The limits of detection for ganciclovir and acyclovir quantitation were 10 ng/ml and 50 ng/ml (signal/noise >3), respectively. Daily fluctuations of plasma standard curves ( n=5) for the ganciclovir and acyclovir samples were small, with relative standard deviations (RSD) of 3.3 and 4.5% ( n=5), respectively. The intra-assay precision for the ganciclovir and acyclovir samples were 6.9 ( n=5) and 5.5% ( n=5), respectively. Inter-assay precision of ganciclovir ( n=3) and acyclovir ( n=3) ranged from 2.6 to 6.8% and 3.5 to 5.0%, respectively. Using this method, the pharmacokinetics and removal of ganciclovir during continuous hemodiafiltration (CHDF) in a liver transplant recipient being treated for severe cytomegalovirus infection was investigated. The mean (±SD) ratio of ganciclovir concentrations at the inlet and outlet of the dialyzer ( C outlet/ C inlet) was 0.56±0.09. The areas under the curves of ganciclovir up to 12 h postdosing (AUC 0→12) at the inlet and outlet of the dialyzer were 12.54 μg h/ml and 7.16 μg h/ml, respectively. The ultrafiltrate of ganciclovir was 16.6 mg. The terminal elimination half-life ( T 1/2) of ganciclovir during CHDF was 3.6 h. These results demonstrate that CHDF effectively removes ganciclovir. Until formal guidelines have been established, ganciclovir or acyclovir dosage should be adjusted according to the results of monitoring of plasma drug concentration. The method described here is suitable for clinical monitoring of plasma ganciclovir or acyclovir levels in solid organ transplant recipients and for use in studies involving pharmacokinetics.

Position paper on therapeutic drug monitoring of antiretroviral agents.

Monitoring drug concentrations in humans to optimize efficacy and reduce toxicity is not a new concept in clinical pharmacology. It has been successfully applied to many different classes of drugs. As a result of considerable concentration and response data, the concept of therapeutic drug monitoring (TDM) has been expanded to certain antiretroviral compounds. In particular, protease inhibitors and nonnucleoside reverse transcriptase inhibitors may be viable candidates for TDM, and limited clinical trial data suggest monitoring plasma concentrations of these agents may indeed clinically benefit patients with HIV infection. A primary distinction between TDM of antiretroviral drugs compared with other drugs is that multiple agents are concomitantly used to treat HIV infection. As with all illnesses that require self-administered drug therapy, poor adherence is a major impediment to success. However, in the treatment of HIV infection, inadequate drug concentrations will result in the appearance or evolution of drug resistance mutations that can endanger present and future drug treatment options. Procedures for sample collection, cross-validation of analytical procedures, and interpretation of assay results should be standardized. More clinical data are needed to confirm this approach and methods of implementing TDM should be further explored. This position paper offers guidelines to aid clinicians who choose to incorporate TDM into the routine care of their patients.

Pronounced cytostatic activity and bystander effect of a novel series of fluorescent tricyclic acyclovir and ganciclovir derivatives in herpes simplex virus thymidine kinase gene-transduced tumor cell lines.

A number of tricyclic acyclovir (ACV) and ganciclovir (GCV) derivatives substituted with bulky lipophilic groups have been identified as potent and highly selective cytostatic agents against herpes simplex virus type 1 (HSV-1)-thymidine kinase (TK) gene-transduced human osteosarcoma and murine mammary carcinoma tumor cells. Although their affinity for HSV-1 TK was inferior to that of ACV or GCV, their cytostatic potency and selectivity was at least as high as observed for the parental ACV and GCV compounds. The tricyclic ACV and GCV derivatives were also endowed with a very pronounced bystander effect in cell culture, albeit at relatively high drug concentrations. Unlike ACV and GCV, the tricyclic purine derivatives are endowed with intrinsically strong fluorescent properties, which allow simple and sensitive monitoring of drug concentrations in biological fluids and tissues. Also, the lipophilicity of the tricyclic purine derivatives is much higher than that of ACV and GCV, and this may allow better uptake of these derivatives from the blood into the central nervous system.

Lack of an effect of topiramate on lamotrigine serum concentrations.

Pharmacokinetic interactions between the older antiepileptic drugs (AEDs) and topiramate (TPM) were assessed during the clinical development of this drug. Lamotrigine (LTG) has become established as an important new drug in treating a wide spectrum of seizure types, but there are no published data on whether LTG serum concentrations change when TPM is added to treatment. Escalating doses of TPM were added to stable LTG treatment in 24 young patients (8-21 years) with epilepsy. Blood samples taken before the morning dose were collected for drug-concentration measurement in all patients before starting treatment with TPM and after stabilisation at each dose escalation. Several patients had been maintained on unchanged therapy with drug-concentration monitoring for many months before introducing TPM, and a sequence of baseline LTG serum concentrations were available on these patients. The mean of all baseline LTG concentrations for the group as a whole was 10.4 +/- 4.4 mg/L compared with 9.7 +/- 4.3 mg/L after addition of TPM. A comparison of last baseline LTG concentration with first test LTG concentration (i.e., after 2 weeks' TPM treatment) gave mean values of 10.7 +/- 4.7 and 10.8 +/- 4.6 mg/L, respectively. The mean LTG concentration for patients while taking their highest TPM dose was 9.5 +/- 4.3 mg/L. The analysis-of-variance modeling for the effect of TPM on LTG concentration yielded a mean LTG concentration ratio (with TPM vs. without TPM) of 94.2%, with a 90% confidence interval of 89.5-99.1%. TPM did not cause a significant change in LTG serum concentration in this group of patients.

The characteristics of side-effects of bromperidol in schizophrenic patients.

The characteristics of the side-effects of bromperidol was investigated in 33 acutely exacerbated schizophrenic patients. The most frequently observed side-effects were extrapyramidal symptoms. Acute dystonia developed in 10 of 33 patients, and the mean age was significantly lower (P < 0.05) in patients with dystonia (27.3 +/- 6.2 years) than that in patients without dystonia (41.5 +/- 12.9 years). Plasma drug concentrations were not associated with side-effects. These findings suggest that acute dystonia is affected by age factor, and that daily dosage or monitoring of drug concentration is unlikely to be a useful marker for the prediction of side-effects during bromperidol treatment.

Population pharmacokinetics of lamotrigine.

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided sparse data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

Microdialysis studies of the middle ear distribution kinetics of amoxicillin in the awake chinchilla

This work was performed to develop an experimental animal model for the study of antibiotic drug distribution into middle ear fluid (MEF) and to evaluate its relevance and significance to the clinical treatment of otitis media (OM). Chinchillas were assigned to normal or infected ear groups after Eustachian tube obstruction (ETO) or direct trans‐bullar inoculation with type 3 Streptococcus pneumoniae. Following survival surgery to implant microdialysis (MD) probes in the jugular vein and middle ear (ME), amoxicillin was given intravenously (iv) as a bolus or infusion. Drug concentrations in blood and MEF were continuously monitored by microdialysis. The measured concentrations were corrected for probe recovery by simultaneous retrodialysis. Multiple MEF and blood sampling was also performed to validate the animal model and MD sampling technique. Bacterial infection was successfully induced 3–7 days after the inoculation, whereas the control group gave negative bacterial culture results. The β‐lactam antibiotic, amoxicillin, exhibited an elimination half‐life of 0.33±0.23 h (n = 9) in chinchilla blood, 1.46±0.50 h (n = 5) and 1.75±0.84 h (n = 4) in MEF of normal and infected ears (p = 0.6), respectively. MEF‐to‐blood amoxicillin concentration ratios at steady state following iv infusion were 0.26±0.06 (n = 5) and 0.28±0.11 (n = 4) for normal and infected ears (p = 0.7), respectively. MD allows continuous monitoring of drug concentration–time profiles in blood and MEF in an awake chinchilla model. The concentrations measured by MD were validated by direct sampling. The ratio of the area under the curve (AUC) of drug concentration in MEF versus time to that in blood after iv bolus doses was less than unity, as was the steady‐state concentration ratio following constant‐rate iv infusion, suggesting an active transport mechanism was involved in the efflux of amoxicillin from the ME of chinchilla. The results of studies involving infected ears were not significantly different from those in normal ears in terms of amoxicillin distribution across the ME mucosal membrane after systemic administration. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2088–2098, 2001

Therapeutic drug monitoring--antiepileptic drugs.

To provide a brief critical review of the basis and contemporary practice of monitoring the concentrations of antiepileptic drugs in biological fluids. The review is based on literature data and observations from clinical practice. As experience has accumulated, monitoring of antiepileptic drug concentrations has come to be applied mainly to certain of the drugs when present in whole plasma. For these drugs there is a reasonably established relationship between drug concentrations and biological effects, but attention still needs to be paid to issues such as the timing of the measurements in relation to drug intake, the presence or absence of steady-state conditions, the presence in plasma of active metabolites and possible nonlinear pharmacokinetics of particular agents, e.g. phenytoin. Plasma antiepileptic drug concentration monitoring is coming to be used in a more thoughtful and critical manner. Lack of adequate knowledge of matters such as the relationship between the plasma concentrations and antiepileptic and toxic effects of the drugs, not only the newer, but also the longer established ones, in particular clinical situations, remains more important than deficiencies in analytical methodology in limiting the clinical usefulness of antiepileptic drug concentration monitoring.

Quinupristin/dalfopristin

Quinupristin/dalfopristin (Q-D) is a synergistic streptogramin combination (30:70 ratio). It has potent in vitro activity against gram-positive pathogens including vancomycin-resistant Enterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus, and drug-resistant Streptococcus pneumoniae, but not Enterococcus faecalis. A minimum inhibitory concentration of 1.0 μg/mL or less, or a zone size greater than 18 mm, indicates susceptibility. Dosing in the United States (7.5 mg/kg) is every 8 hours for serious or life-threatening VREF infections and every 12 hours for complicated methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes skin or skin structure infections. To minimize side effects, Q-D is given via a central line for a period of at least 60 minutes. Pediatric use is by compassionate or experimental protocol. Q-D is 80 percent excreted in bile and stool. Q-D use with cytochrome P450 3A4 substrate drugs (eg, cyclosporine A) requires drug concentration monitoring. Avoid concomitant corrected QT interval (QTc)-prolonging drugs metabolized by cytochrome P450 3A4. Efficacy in treating VREF is approximately 70 percent, with underlying patient conditions affecting outcome. Adverse effects include pain and inflammation at the infusion site (~40%), hyperbilirubinemia (~25%), arthralgia and myalgia (~7%), nausea and vomiting (~5%), and diarrhea (~3%). Copyright © 2001 by W.B. Saunders Company

Pharmacokinetics of tetramethylpyrazine in rat blood and brain using microdialysis

Since the central nervous acting agent, tetramethylpyrazine, is reported to have appreciable blood–brain barrier penetrability, a design allowing simultaneous and continual monitoring of drug concentrations in blood and brain was employed to study the distribution of intravenously administered tetramethylpyrazine (10 mg kg −1). The system consisted of two microdialysis probes, each optimally constructed for sampling of the respective body fluids, inserted into the right jugular vein and striatum of male Sprague–Dawley rats. The probes were perfused with appropriate media at rates optimized for recovery. Dialysates were automatically collected using a microfraction collector and drugs were analyzed by high performance liquid chromatography (HPLC) with ultra violet (UV) detection. Results indicate that both blood and brain pharmacokinetics of unbound tetramethylpyrazine fit best to a two-compartment model. The elimination half-life of tetramethylpyrazine in rat blood and brain were 82.1 and 184.6 min, respectively. Increasing brain/blood concentration ratios suggested that tetramethylpyrazine effectively penetrated the blood–brain barrier.

Quantification of Benzoic, Phenylacetic, and Phenylbutyric Acids from Filter-Paper Blood Spots by Gas Chromatography–Mass Spectrometry with Stable Isotope Dilution

An important treatment of hyperammonemia in urea cycle disorders is the stimulation of alternative pathways for nitrogen excretion (1). Salts of benzoic acid (BA), phenylacetic acid (PAA), and phenylbutyric acid (PBA) have been found to be useful vehicles for the elimination of nitrogen by alternative pathways (2)(3)(4). BA is conjugated with glycine to form hippurate, which is efficiently excreted in the urine. PBA is metabolized in the liver to phenylacetyl-CoA, which is then conjugated with glutamine to form phenylacetylglutamine and subsequently excreted in the urine. Furthermore, benzoate has been used to treat nonketotic hyperglycinemia (5), salts of PBA and PAA are used in clinical trials as anticancer agents (6)(7)(8)(9), and PBA has been found to stimulate fetal hemoglobin production and can potentially be used for treatment of hemoglobinopathies (10)(11). However, two patients have died in the US after being given the wrong doses of sodium benzoate and sodium phenylacetate (12), documenting the risk of toxicity, which could potentially be reduced by drug concentration monitoring. HPLC assays for PAA and PBA in plasma have limited sensitivity (4). A gas chromatographic–mass spectrometric method had improved sensitivity (13), but the method did not use stable isotopes as internal standards and the clinical utility of the method was not documented. Here, we describe a rapid, precise, and convenient method to measure blood concentrations of these drugs using dried filter-paper blood spots. BA, PAA, and PBA were purchased from Sigma-Aldrich Co. [ring- d 5]-BA, [ring- d 5]-PAA, and [2,2,3,3- d 4]-4-PBA were purchased from Cambridge Isotope Laboratories. Regisil RC-3 [ N , O -bis-(trimethylsilyl)trifluoroacetamide containing trimethylchlorosilane (10:1 by volume; BSTFA-TMCS)] was purchased from Regis Chemical Co. Blood collection cards (cat. no. 10538414) were purchased from Schleicher & Schuell. Blood was …

Drug Concentration Monitoring of Immunosuppressive Agents

Several new immunosuppressive agents have recently been approved for use in solid organ transplantation. Many of these agents have narrow therapeutic ranges, which necessitates drug concentration monitoring in order to optimise efficacy, minimise toxicity and individualise dosages. Some of the lessons learned with the clinical use of the revolutionary agent cyclosporin have been applied to the newer agents tacrolimus and sirolimus. The agent mycophenolate mofetil has been in clinical use without widespread drug concentration monitoring; however, recent data suggest that therapeutic monitoring may improve clinical outcomes, especially in certain high risk subsets of patients. This review focuses on the literature published to date on drug concentration monitoring of the newer immunosuppressive agents - tacrolimus, mycophenolate mofetil and sirolimus. In addition, pertinent aspects of the clinical pharmacokinetics and metabolism of each agent are reviewed.

Decreased exposure to saquinavir in HIV-1-infected patients after long-term antiretroviral therapy including ritonavir and saquinavir.

To explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir. The pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily. The first study day was 4-12 months (median 7 months) after the start of the current regimen. The second study day was 9-15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was -30% (range -79 to +11%; P = 0.06). Median change in maximum plasma concentration was -40% (range -62 to +34%; P = 0.09). The median change in area under the plasma concentration versus time curve over 0-8 h was -33% (range -53 to +21%; P = 0.06). The exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients.

Age-related changes in protein binding of drugs: implications for therapy.

The plasma protein binding of drugs, particularly those that are highly bound, may have significant clinical implications. Although protein binding is a major determinant of drug action, it is only one of a myriad of factors that influence drug disposition. The extent of protein binding is a function of drug and protein concentrations, the affinity constant for the drug-protein interaction and the number of protein binding sites per class of binding site. Age-related changes in protein binding are usually not clinically important in drug therapy. Albumin levels are generally decreased in the elderly, whereas alpha1-acid glycoprotein levels are not altered by age per se. Alterations in plasma protein binding that occur in the elderly are generally not attributed to age, but rather to physiological and pathophysiological changes or disease states that may occur more frequently in the elderly and most often account for altered protein binding. Age-related physiological changes, such as decreased renal function, decreased hepatic function and decreased cardiac output, generally produce more clinically significant alterations in drug disposition than that seen with alterations in drug plasma protein binding. An understanding of the inter-relationships between drug concentrations, protein binding, the physiology of aging, disease, pharmacokinetics and pharmacodynamics is necessary for effective therapeutic monitoring. Monitoring of unbound drug concentrations simplifies these relationships and provides the fundamental information needed for dosage regimen development and adjustment. Drug therapy in the elderly should be individualised taking into account all of these factors.

Elevated Free Fractions of Valproic Acid in a Heart Transplant Patient with Hypoalbuminemia

To report a case demonstrating the importance of monitoring unbound valproic acid (VPA) serum concentrations in a patient with hypoalbuminemia. A 53-year-old white woman status-post heart transplantation was admitted to the hospital for declining cardiac function, possible rejection, and increased lethargy requiring intubation. An extensive workup of the patient's profound lethargy was initiated, including an evaluation of her VPA regimen. Initially, VPA dosages were adjusted based on the total serum concentration of VPA. Hypoalbuminemia compounded with increased lethargy prompted the measurement of unbound serum concentrations of VPA. The VPA dosage was then adjusted based on the unbound rather than the total VPA serum concentration; the patient eventually improved and was discharged from the hospital. Lethargy is a concentration-related adverse effect of VPA. The nonlinear pharmacokinetic and protein saturation characteristics of VPA may result in nonproportional elevations in unbound drug, and subsequent increases in adverse effects, when dosage adjustments are based solely on measurement of total VPA serum concentrations in patients with hypoalbuminemia. This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

Anticonvulsants and breast feeding: a critical review.

Progress in the diagnosis and management of seizure disorders and the availability of effective anticonvulsive medications has enabled increasing numbers of epileptic women of child-bearing age to raise families. Breast feeding, which these women may wish to choose, provides health, nutritional, immunological, developmental, social, economic and environmental benefits. The traditional anticonvulsants, such as phenytoin, carbamazepine and valproic acid (valproate sodium), are generally considered safe for use during breast feeding; however, observation for adverse effects is recommended. The use of phenobarbital while breast feeding is controversial because of its slow elimination by the nursing infant. The newer anticonvulsants, such as clobazam, felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin, are used mainly as adjunctive therapy. Data on the use of these drugs in pregnancy and lactation, and regarding long term effects on cognition and behaviour, are sparse. Weighing the benefits of breast feeding against the potential risk to the nursing infant, breast feeding is considered to be safe when the mother is taking carbamazepine, valproic acid or phenytoin. Infant monitoring for potential adverse effects is advisable when the mother is taking phenobarbital, clobazam, gabapentin, lamotrigine, oxcarbazepine or vigabatrin. Monitoring of infant serum drug concentrations is advisable but not compulsory. The use of felbamate, tiagabine and topiramate during breast feeding should await further study.

Anticonvulsant use during lactation.

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested. Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects. In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.

Tear/Plasma Urea Ratio as a Correction Coefficient for Drug Monitoring in Tears

Objective: To formulate the tear/plasma urea ratio as a coefficient for correcting drug concentrations in tears. Subjects and Methods: Urea concentrations were measured in 14 paired tear and plasma samples from seven healthy adult volunteers (3 women, 4 men). A second sample was obtained one hour after the first. The samples were simultaneously assayed for urea concentrations by a urease method (Boehringer Mannheim). Results: Our data show a highly significant correlation between tear and plasma urea concentrations in all the samples (r = 0.985, p &lt; 0.001; r = 0.928, p &lt; 0.003; and r = 0.944, p &lt; 0.001 in the first, second, and total collection of samples, respectively). In all paired tear and plasma samples, urea content in tears was higher than in plasma (p &lt; 0.001, p &lt; 0.015, and p &lt; 0.001 in the first, second, and total samples, respectively). The tear/plasma urea ratio in all samples ranged from 1.016 to 1.225 (mean ± SD 1.126 ± 0.068) and had a significant negative correlation (r = −0.538; p &lt; 0.05) with tear volume (range 25–155 μL, mean ± SD 83.9 ± 42.6). Conclusions: Higher urea concentrations in tears than in plasma and a negative correlation between tear volume and the tear/plasma urea ratio indicate that tear evaporation and, consequently, tear concentration occur during sample collection. These data and the highly significant correlation between tear and plasma urea concentrations justify the use of the tear/plasma urea ratio as a correction coefficient for monitoring drug concentrations in tears.

Antipsychotics and breast-feeding: a review of the literature.

Many women with mental illnesses would like to breast feed their infants. In light of the limited but rapidly growing data, it seems that in some cases the possible physiological and psychological benefits may outweigh putative risks. All antipsychotics are secreted into breast milk but the concentrations and effects vary. There is a subgroup of mothers with mental illnesses who want to breast feed their infants and who are receiving a single established antipsychotic drug (principally, haloperidol or chlorpromazine) at the lowest possible clinically effective dose. As a tentative conclusion, this group could experience benefits from being able to nurse which would outweigh the risk of exposing their babies to very small amounts of antipsychotic drugs. However, larger study groups with longer follow-up periods would be required to confirm this tentative conclusion. Those mothers who require 2 or more antipsychotic drugs simultaneously and those taking one drug, but at the upper end of the recommended dose range, should not be advised to breast feed. Safety considerations suggest that women taking atypical antipsychotics would be advised not to breast feed because of the limited experience with these agents. When mothers taking antipsychotic drugs do nurse, it is desirable to monitor drug concentrations in breast milk and in the infants themselves. Close monitoring of the infant is essential.

Clinically significant pharmacokinetic drug interactions between antiepileptic drugs.

Pharmacokinetic interactions between antiepileptics represent a major potential complication of epilepsy treatment because drug combinations are common. This review discusses pharmacokinetic drug interactions of clinical significance involving antiepileptics and cytochrome P450 (CYP). Most commonly used antiepileptics are eliminated through hepatic metabolism, catalysed by the enzymes CYP2C9, CYP2C19 and CYP3A4 and uridine diphosphate glucuronosyltransferase (UDGPT). Antiepileptics are associated with a wide range of drug interactions, including hepatic enzyme induction and inhibition. Phenytoin, phenobarbiral, primidone and carbamazepine induce CYP and UDPGT enzymes while valproic acid inhibits them. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential and careful dosage adjustments based on serum drug concentration monitoring and clinical observation are the main methods for reducing the risks associated with these interactions.