Showing papers in "Therapeutic Drug Monitoring in 1991"

Clinical pharmacokinetics of morphine

Abstract: Morphine (M) is recommended by the World Health Organization as the treatment of choice for moderate-to-severe cancer pain Development of sensitive radioimmunoassays (RIA) and high-performance liquid chromatography in the past 20 years has allowed study of the pharmacokinetics of M, which remain incompletely understood Data derived by RIA must be interpreted with caution due to cross-reactivity with anti-sera by metabolites, impairing assay specificity The pharmacokinetics of M have been determined for various clinical situations, but there is large interpatient variability for most parameters M is readily absorbed from all routes of administration, except transdermal, and it can be injected spinally Peak plasma levels are achieved within 15-20 min of intramuscular and subcutaneous administration, and within 30-90 min after oral Peak levels after oral administration are much lower than after parenteral routes, since oral M undergoes extensive first-pass metabolism in the liver With repeated administration, the oral-parenteral relative potency ratio is 1:3 M can be administered epidurally or intrathecally and has also been given intracerebroventricularly Epidural M enters the subarachnoid space, but is also absorbed into the systemic circulation Only 5% of a dose crosses the dura M administered in the lumbar region is quickly redistributed in the cerebrospinal fluid in a rostral direction, explaining the high incidence of systemic side effects following spinal administration After absorption, M is rapidly and widely distributed and crosses the blood-brain barrier With therapeutic doses, plasma protein binding is only 20-35%, and the volume of distribution is 1-6 L/kg The primary site of M metabolism is the liver, and the dose should be reduced in patients with liver disease Glucuronidation is the main metabolic pathway, but the principal metabolite, morphine-3-glucuronide (M3G), is inactive Morphine-6-glucuronide (M6G) is produced in smaller amounts than M3G, but is pharmacologically active and many times more potent than M The ratio of M6G to M in plasma, after a dose of M, is approximately 10:1, and the ratio does not change with increasing doses or prolonged treatment Normorphine (NM) is also active, and is formed to a greater extent after oral administration; it is not, however, usually found in plasma NM may be neurotoxic M and its metabolites are excreted by the kidney, but urinary free M accounts for less than 10% of an administered dose In patients with renal insufficiency, the metabolites accumulate, though M itself is still excreted(ABSTRACT TRUNCATED AT 400 WORDS)

Factors influencing the pharmacokinetics of cyclosporine in man

Abstract: The clinical use of cyclosporine A (CsA) is complicated by large intra- and interindividual variabilities in its pharmacokinetics. Several factors contribute to these variabilities. This review aims at describing these factors and their relative contribution in the clinical situation. Cyclosporine A has a highly variable absorption. The absorption is dependent on the liver function, bile flow, and gastrointestinal status. A large fatty meal may increase the absorption of CsA. Impaired absorption is observed postoperatively. The vehicle or dosage form is of no importance for the absorption. The distribution of CsA is mainly influenced by the lipoprotein concentration in plasma and to a lesser extent by the haematocrit. However, age, gender, and obesity are of no clinical importance for the distribution. The metabolism is presumably genetically determined and the rate of metabolism varies greatly between individuals. Furthermore, the rate of metabolism is age-related and may be affected by concomitant medication. Factors of limited importance for the metabolism include sex, lipoprotein pattern, and drug concentration. Factors such as time after transplantation, haemodialysis, haematocrit, obesity, and uremia are not associated with altered metabolism. Thus, the major factor for the intraindividual variability in CsA kinetics is the variable absorption, whereas the major cause for the interindividual variability supposedly is the inherited capacity to metabolize the drug. The factors mentioned above and other factors, found to be of minor or no importance for the kinetics of CsA, are discussed in detail.

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans.

Abstract: Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)

A simple, rapid method for the simultaneous determination of morphine and its principal metabolites in plasma using high-performance liquid chromatography and fluorometric detection.

Abstract: This article describes a high-performance liquid chromatography (HPLC) method for the simultaneous determination of morphine (M) and its principal metabolites morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), and normorphine (NM) in plasma. All four compounds are extracted from plasma using a C8 solid-phase extraction column, separated by reverse-phase HPLC on a C18 analytical column, and detected by spectrofluorometry at 210 nm excitation wavelength. The method takes advantage of the compounds' native fluorescence, so that derivitization is not required. Samples have been quantified over a concentration range of 25-100 ng/ml M and NM, 50-200 ng/ml M3G, and 100-300 ng/ml M6G, using nalorphine (500 ng/ml) as internal standard. Within-run and between-run errors were less than 10% for morphine and less than 13% for all the metabolites. The lower limit of quantitation for morphine is 10 ng/ml. The accuracy of the method was confirmed by including quality controls fitted to the standard curves of each compound. The assay described in this article represents a simplification of previous versions of the method, which included cumbersome extraction procedures and multiple detectors. For the first time, an internal standard has been employed. The assay is reliable and easy to use and can be performed in any therapeutic drug monitoring laboratory.

The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography.

Abstract: SummaryA high performance liquid chromatographic method for the simultaneous quantitation of clozapinea member of the dibenzodiazepine class of antipsychotic drugsand its reduced metabolite in human plasma has been developed. Clozapine and N-desmethylclozapine are concentrated from blood samples by

Concentration-response relationship in paroxetine treatment of diabetic neuropathy symptoms: a patient-blinded dose-escalation study.

Abstract: A single-blind dose-escalation study with the selective serotonin reuptake inhibitor paroxetine was conducted in 19 diabetic patients with neuropathy symptoms. The effect of treatment was evaluated by self-rating using visual analog scales. After an initial placebo period, paroxetine doses were increased from 10 mg/day in 10 mg steps, until the dose was 30-70 mg/day. In all except four patients, there was a marked relief of symptoms. Plasma concentrations of paroxetine above 300-400 nM were required to insure maximal relief in the majority of patients responding on paroxetine, but a considerable interindividual variation was observed (10-800 nM, median of 195 nM). The therapeutic effect appeared to increase gradually as the plasma concentration increased. The great interindividual variation in the pharmacokinetics of paroxetine was confirmed, but as the effect is maximal within approximately 1 week, and the drug is nontoxic, it may be clinically feasible simply to titrate the dose from 20 mg/day until the maximal effect is achieved. However, it is advised that titration to an effect, in diabetic neuropathy using doses above 50 mg/day, be undertaken with care as there is limited experience with doses above this level in any population. The beneficial effect of paroxetine appeared to be maintained unaltered during an additional 1 month open-label treatment on optimal paroxetine doses.

Outpatient management of warfarin therapy : comparison of computer-predicted dosage adjustment to skilled professional care

Abstract: In a prospective, randomized clinical trial, we compared the accuracy of warfarin dosage-adjustments predictions using a computer program to the skill of an experienced anticoagulation nurse-specialist The computer program predicts the steady state warfarin dose by applying Bayesian forecasting techniques to a mathematical model of the dynamic pharmacologic response to warfarin Fifty patients who were receiving chronic warfarin therapy and who required a dosage adjustment because their prothrombin time was greater than or equal to 2 s away from their target prothrombin time were enrolled The baseline characteristics of each group were similar, including the mean of the absolute value of the differences between initial prothrombin times and corresponding target prothrombin times After a new a new warfarin dose was predicted, the prothrombin time was measured at least 7 days after dosage adjustment Overall, the results in each group were comparable There was no significant difference between groups and the mean of the absolute value of the differences between final prothrombin times and target prothrombin times, nor was there a difference in the proportion of patients who had a final prothrombin time within 2 s of the target prothrombin time We conclude that the accuracy of warfarin dosage adjustments made using computer modeling is comparable to the skill of an anticoagulation nurse-specialist

Immunofluorometric assay for lamotrigine (Lamictal) in human plasma.

Abstract: An immunofluorometric assay (IFA) has been developed for the potential antiepileptic agent, lamotrigine (Lamictal). The assay involves competition between lamotrigine free in solution and bound to a bovine thyroglobulin conjugate on the surface of microtiter strip wells for a limited amount of polyclonal lamotrigine antisera. The end-point of this reaction, which indicates the concentration of lamotrigine present in the solution under analysis, is detected by adding Eu(3+)-labelled anti-rabbit IgG, followed by an enhancement solution to produce a fluorescent product. Thus, the higher the concentration of lamotrigine in the sample, the less intense the fluorescence produced. The assay displays minor cross-reactivity (0.05%) by the major glucuronide metabolite (in humans) and moderate cross-reactivity (2.7%) by a minor N-oxide metabolite (in rats) of the parent drug. No interference from these sources in the analysis of plasma samples from clinical trials was demonstrated by comparative sample analysis by IFA and high-performance liquid chromatography. Intraassay accuracy and precision were excellent, greater than 90% and less than 5% coefficient of variation (CV), while interassay accuracy was greater than 95% and interassay precision (CV) was 8.8-17.0%. This assay is suitable for analysis of lamotrigine in plasma samples collected during clinical trials.

Trace analysis of methotrexate and 7-hydroxymethotrexate in human plasma and urine by a novel high-performance liquid chromatographic method.

Abstract: A new high-performance liquid chromatographic method for the quantitative determination of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7-OHMTX) in blood plasma and urine was developed. The method utilized a solid-phase extraction procedure (Certify II cartridges) for the simultaneou

Concentrations of phosphorylated zidovudine (ZDV) in patient leukocytes do not correlate with ZDV dose or plasma concentrations.

Abstract: Zidovudine (ZDV) elicits its antiviral effect through intracellular metabolism to the 5'-triphosphate, which interferes with viral replication. Monitoring of the active metabolites of ZDV in cells could lead to an intracellular therapeutic range. This study was performed to determine whether a radioimmunoassay, previously used for in vitro quantitation of total phosphorylated ZDV inside peripheral blood leukocytes, could be used for similar determinations in patient samples. The relationship between ZDV dose, plasma concentrations, and intracellular metabolite concentrations was also examined. Ten-milliliter blood samples were drawn from each of 13 human immunodeficiency virus-infected patients and were assayed. Intracellular concentrations of phosphorylated ZDV ranged from 0.33 to 3.54 pmol/10(6) cells, similar to those observed in vitro. Phosphorylated ZDV was independent of dose, and did not correlate with plasma concentrations. Intracellular concentration in the patient population as a whole did not change during the 4-h dosing interval, while plasma concentration decayed normally. Later determinations in the same patients gave intracellular values within 31% of earlier values. Intraassay variability was less than 10%. Thus, the method is valid for measurement of phosphorylated ZDV in patient cells. Although individual concentrations showed no clear change during the 3-month study period, intracellular concentrations decreased with increasing length of therapy (up to 3 years) in the population as a whole. This suggests a decreased cellular ability to phosphorylate ZDV after prolonged exposure to drug. The lack of intracellular decay implies a half-life longer than the 1-h half-life of plasma ZDV. These data suggest that smaller doses or longer dosing intervals might maintain intracellular concentrations once steady state is achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Fat body mass and pharmacokinetics of oral 6-mercaptopurine in children with acute lymphoblastic leukemia

Abstract: To evaluate the reasons for the wide variability in bioavailability of orally administered 6-mercaptopurine in children with acute lymphoblastic leukemia, we studied several pharmacokinetic parameters of the drug in 18 affected children receiving remission maintenance therapy, and compared them with their anthropometric data and with the results of intestinal function tests. No correlation was found between estimates of small intestinal absorption (the oral lactose tolerance test and 1 h blood xylose test) and 6-mercaptopurine serum levels. Of the anthropometric measurements considered, only the weight/height percentile (an index of the fat body mass) strongly and linearly correlated with the area under the curve of 6-mercaptopurine. The dose of 75 mg of 6-mercaptopurine/m2 of body surface resulted in higher serum concentrations in children below the 75th percentile than in those with a weight/height ratio exceeding the 75th percentile. In conclusion, these data caution about the risk of underdosing 6-mercaptopurine in overweight children when administering it on the basis of body surface area.

Clinical response in epilepsy in relation to total and free serum levels of phenytoin.

Abstract: SummaryThe relationships between total and free serum concentrations of phenytoin and the clinical control of seizures were investigated retrospectively in 114 patients. Total phenytoin levels were measured by enzyme-modified immunoassay (EMIT), and the free fraction by ultrafiltration at 37°C using

Plasma distribution of cyclosporine within lipoproteins and "in vitro" transfer between very-low-density lipoproteins, low-density lipoproteins, and high-density lipoproteins.

Abstract: Cyclosporine A (CsA) is a very lipophilic, immunosuppressive peptide that is highly bound (greater than 95%) in plasma. Approximately 50% of the drug is bound to lipoproteins and the remainder to erythrocytes. Neither the therapeutic nor the toxic effects of cyclosporine have been correlated with the free drug concentration. It has been proposed that low-density lipoprotein (LDL) delivers CsA to T-lymphocytes via the LDL receptor pathway, where it then produces its therapeutic effects. We have found that our patients chronically treated with cyclosporine carry as much or more CsA in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL) as they do in LDL. In addition, as previously reported, those patients with high VLDL carried the major portion of CsA in their VLDL subfraction. Moreover, the triglyceride-rich lipoproteins (VLDL and IDL) were found to contain much more CsA per mg of lipid than either HDL or LDL. An acute drug challenge led to the same CsA distribution as that seen in the chronically treated patients. "In vitro" incubations of lipoproteins containing CsA with lipoproteins from untreated individuals demonstrated a different relative affinity of CsA for the various lipoproteins than would be predicted from the plasma distribution: LDL greater than VLDL greater than HDL. We propose that the plasma distribution of CsA is determined by factors other than simple diffusion between the lipoprotein particles. Possible mechanisms would include (a) plasma factors that augment or inhibit CsA transfer or (b) metabolic processing of the lipoproteins that move CsA from one lipoprotein to another.

Intraindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.

Abstract: Summary:The intraindividual variability of salivary carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations was studied in six healthy male volunteers. During three consecutive 1-week phases, subjects took one of the antiepileptic drugs (AED) for 5 days. Nine saliva and nine bloo

Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine, and mephenytoin.

Abstract: A 34-year-old man with bipolar manic depressive illness suffered from severe adverse effects during treatment with amitriptyline, 50 mg/day. It was subsequently shown that the patient was a slow metabolizer of amitriptyline. However, he tolerated a dose of 200 mg of imipramine/day, which was necessary in order to reach a therapeutic level of about 900 nM for imipramine plus desipramine. Since both antidepressants are subject to the genetic sparteine/debrisoquine oxidation polymorphism, the patient was phenotyped with sparteine. The test performed during paroxetine treatment indicated that the patient was a poor metabolizer. Subsequent tests performed during a drug-free period, however, showed the patient to be an extensive metabolizer, with a sparteine metabolic ratio (MR) of 1.7 and 2.8 and debrisoquine MR of 2.3. It was subsequently shown that paroxetine is a potent, competitive inhibitor of 1'-hydroxybufuralol formation in a human liver microsome preparation (K1 approximately 800 nM). This patient thus illustrates two problems: (a) the erroneous phenotyping due to concurrent medication, and (b) the existence of a very slow amitriptyline elimination apparently not related to the sparteine/debrisoquine oxidation polymorphism.

Enantioselective hydroxylation of nortriptyline in human liver microsomes, intestinal homogenate, and patients treated with nortriptyline.

Abstract: The enantioselectivity of hydroxylation of nortriptyline (NT) to E-10-hydroxynortriptyline (E-10-OH-NT) was studied in human liver microsomes, intestinal homogenate, and patients treated with NT. The rate of formation of (-)-E-10-OH-NT was higher than that of (+)-E-10-OH-NT both in the liver microsomes and in the intestinal homogenate. Quinidine, a prototype competitive inhibitor of the cytochrome P450IID6 ("debrisoquin hydroxylase"), inhibited the formation of (-)-E-10-OH-NT in a concentration-dependent manner in liver microsomes, while the formation of (+)-E-10-OH-NT was hardly affected. This indicates that P450IID6 catalyzes the hydroxylation of NT in a highly enantioselective manner to (-)-E-10-OH-NT in the liver. Another P450 isozyme besides IID6 seems to be responsible for the formation of the (+)-enantiomer in the liver. In intestinal homogenate, the formation of both enantiomers of E-10-OH-NT was inhibited to about the same extent by quinidine, the maximum inhibition being much less than in the liver. In the urine of six patients treated with NT, the (-)-enantiomer accounted for 91 +/- 2% of the unconjugated E-10-OH-NT, and for 78 +/- 6% of the glucuronide conjugates. The study shows that NT is hydroxylated in a highly enantioselective way, probably catalyzed by the polymorphic P450IID6, to (-)-E-10-OH-NT both in vitro in human liver as well as in vivo in patients treated with the drug.

Determination of vigabatrin in plasma by reversed-phase high-performance liquid chromatography.

Abstract: A method is described for the determination of vigabatrin in 50 microliters of plasma by isocratic high-performance liquid chromatography using fluorescence detection. The procedure involves protein precipitation with methanol followed by precolumn derivatisation with o-phthaldialdehyde reagent. Separation of the derivatised vigabatrin was achieved on a Microsorb C18 column using a mobile phase of 10 mM orthophosphoric acid:acetonitrile:methanol (6:3:1) at a flow rate of 2.0 ml/min. Assay time is 15 min and chromatograms show no interference from commonly coadministered anticonvulsant drugs. The total analytical error within the range of 0.85-85 micrograms/ml was found to be 7.6% with the within-replicates error of 2.76%. The minimum detection limit was 0.08 micrograms/ml and the minimum quantitation limit was 0.54 micrograms/ml.

Carbamazepine age-dose ratio relationship in children.

Abstract: Steady-state plasma carbamazepine (CBZ) concentrations were measured in 196 pediatric inpatients taking CBZ alone or CBZ combined with other drugs. The steady-state CBZ concentrations divided by the daily administered dose (dose ratio, reciprocal of apparent clearance) increased significantly (r = 0.183, p less than 0.01) with age. The correlation between dose and CBZ concentration, while significant (r = 0.265, p = 0.023), was weak because of wide interindividual differences in dose ratio. There was a negative correlation between CBZ daily dose and CBZ dose ratio. This negative correlation was significant in children 4-6 (r2 = 0.481, p less than 0.01), 7-11 (r2 = 0.399, p less than 0.01), and greater than 11 years of age (r2 = 0.401, p less than 0.01), but not in children less than 4 years of age (r2 = 0.172, p greater than 0.1). The CBZ dose ratio was significantly (p less than 0.001) lower in patients taking CBZ in combination with more than one other antiepileptic drug compared with those on CBZ monotherapy. No significant (p greater than 0.1) difference in CBZ dose ratio was found between male and female patients. These findings suggest that CBZ clearance was influenced by age, dose, and comedication with more than one other antiepileptic drug but not sex. The concentration necessary for efficacy is a clinical, not an analytical decision. However, the dose-concentration relationships show that recommended pediatric CBZ doses of 10-30 mg/kg/day are not enough to attain published therapeutic CBZ concentrations in many children.(ABSTRACT TRUNCATED AT 250 WORDS)

High-performance liquid chromatographic determination of 12 antiarrhythmic drugs in plasma using solid-phase column extraction

Abstract: Monitoring of plasma concentrations of antiarrhythmic drugs may assist in individualizing dosage regimens and in assessing patient compliance. A rapid high-performance liquid chromatographic assay using solid-phase column extraction was developed for the following antiarrhythmic drugs: amiodarone, aprindine, disopyramide, flecainide, lidocaine, lorcainide, mexiletine, procainamide, propafenone, sotalol, tocainide, and verapamil. As most of the antiarrhythmic drugs are basic compounds, good adsorption on the extraction columns was obtained by alkalinization; aprindine, however, was applied at neutral pH and amiodarone at pH 3.5. After washing with water, the compounds were eluted with methanol, but amiodarone was eluted with a mixture of acetonitrile and acetate buffer at pH 5 (8/2, vol/vol). Most of the eluates were evaporated to dryness and reconstituted in the mobile phase; for amiodarone, disopyramide, and tocainide, direct injection onto the column was performed. Separation was done on a Spherisorb hexyl 5 mu column (150 x 4.6 mm I.D.) and the mobile phases consisted of mixtures of acetonitrile or methanol with phosphate or acetate buffers at different pH values. Detection was performed by UV or fluorescence detector. Coefficients of variation were lower than 10% with good recovery and linearity in the expected therapeutic ranges.

Quantitation of fansimef components (mefloquine + sulfadoxine + pyrimethamine) in human plasma by two high-performance liquid chromatographic methods

Abstract: Two simple, precise, and selective high-performance liquid chromatographic methods are described for the simultaneous quantitation of mefloquine (MQ) plus pyrimethamine (PYR) or sulfadoxine (SDX) plus its principal metabolite N4-acetylsulfadoxine (N4SDX) in human plasma. After a single-step extraction, MQ plus PYR and SDX plus N4SDX including internal standards were separated using ion-paired and ion-suppression chromatography. Total run times for the assays were less than 12 min. Intraassay and interassay precision of the methods expressed as the coefficients of variation were less than 9% in plasma for the four compounds. The extraction recovery averaged 98% for MQ, 97% for PYR, 96% for SDX, and 81% for N4SDX. Plasma concentrations of the four compounds in a pediatric patient after a single oral dose of Fansimef (MQ + SDX + PYR) were determined to demonstrate the clinical application of the methods.

Area under the curve monitoring of cyclosporine therapy : the early posttransplant period

Abstract: Summary: The impact of a new monitoring strategy on whole blood concentrations of cyclosporine measured by a specific monoclonal radioimmunoassay was investigated in a group of 37 renal transplant patients. Before transplantation, the patients received a standard intravenous (i.v.) and oral (p.o.) test dose of cyclosporine to calculate their individual i.v. and p.o starting dose rates to achieve a certain target steady-state cyclosporine concentration. After transplantation, the designated i.v. dose rate was continuously infused for 2 days, at which time the steady-state concentration was measured. Then, the designated oral dose for 24 h was administered while the infusion was continued at an unaltered rate. The oral absorption of cyclosporine was documented by blood samples over the following 8 h. If necessary, this overlap of i.v. and p.o. dosing was repeated until blood concentrations of cyclosporine rose at least 700 ng/ml over the steady-state concentration. By that time, the infusion was stopped and oral dosing continued. Individualized infusions led to steady-state concentrations within a range that did not exceed 1.1 times the median concentration of 472 ng/ml. Standard infusion rates in the past produced a much wider range of steady-state concentrations (9.6 times the median). Individualized infusions reached the target steady-state concentration with a significant positive bias of 17% (SEM = ≤32%, range of −36 to + 105%). Individualized oral doses reached the target average steady-state concentration (calculated by dividing the area under the concentration-time curve by the dosing interval) with an inferior precision (median = 2.6%, range of −54 to + 130%) but without a positive or negative bias. Until 14 days after transplantation, 88% of the patients showed satisfactory oral absorption of cyclosporine; the remaining 12% were kept on infusions for up to 1 month. The new monitoring strategy rendered immunosuppression with cyclosporine and prednisone a safe and effective therapy after renal transplantation.

Indomethacin pharmacokinetics in neonates : the value of volume of distribution as a marker of permanent patent ductus arteriosus closure

Abstract: SummaryIndomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure, Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent d

Quantitation of oxycodone in human plasma using high-performance liquid chromatography with electrochemical detection.

Abstract: An original, highly sensitive and specific high-performance liquid chromatographic (HPLC) assay has been developed for the measurement of oxycodone in human plasma with a detection limit of 10 ng/ml using a 1.0-ml plasma sample. Plasma samples were initially acid-washed and then extracted twice at pH 10 with butyl chloride. Oxycodone and codeine (internal standard) were eluted with a mixture of methanol, acetonitrile, and 0.01 pH 7 phosphate buffer to which 40 mg/1 of cetyltrimethylammonium bromide (cetavlon) was added at ambient temperature and detected with electrochemical detection. The addition of cetavlon to the mobile phase markedly reduced the interaction between oxycodone and Si-OH groups on the stationary phase of the HPLC column, so that the organic content of the mobile phase could be reduced from 80 to 25%. Quantitation was achieved using the peak height ratio of oxycodone to codeine. The assay is currently being used for the study of oxycodone pharmacokinetics after single oral doses of 10 and 20 mg and single rectal doses of 30 mg.

Measurement of ciprofloxacin in human plasma, whole blood, and erythrocytes by high-performance liquid chromatography

Abstract: A simple, rapid, and accurate high-performance liquid chromatographic method using fluorescence detection is described for the measurement of ciprofloxacin in plasma, whole blood, and erythrocytes. Ciprofloxacin and the internal standard difloxacin were separated on a mu-Bondapak C18 column (30 cm x 3.9 mm inside diameter, 10 microns particle size), using a mobile phase of 0.1 M phosphate buffer (pH 2.5):acetonitrile (75:25, vol/vol). The retention times were 5.1 min for ciprofloxacin and 7.9 min for difloxacin. The compounds were extracted from the three biological fluids using protein precipitation followed by a single-step liquid-liquid extraction. The assay is precise, with interassay coefficients of variation of less than or equal to 9.1% and an accuracy of less than or equal to 7.4% at 0.5 and 5.0 micrograms/ml (n = 5). The mean extraction recoveries of ciprofloxacin in plasma, whole blood, and erythrocytes were 84.4, 63.9, and 48.0%. The limit of detection for ciprofloxacin is 25 ng/ml. Ciprofloxacin concentrations in the three biological fluids were measured in patients with uncomplicated falciparum malaria to demonstrate the application of the method.

Lack of effect of the calcium antagonist isradipine on cyclosporine pharmacokinetics in renal transplant patients.

Abstract: Hypertension has emerged as a frequent side effect in transplant recipients on effective doses of cyclosporine (CsA). To control hypertension in renal transplant patients, calcium channel blockers have been used; some of these, however, have been shown to cause significant increases in CsA levels. These findings point out that possible interactions of each calcium antagonist with CsA deserve investigation. We performed an open, placebo-controlled study in 12 stable renal transplant recipients to determine whether short-term isradipine influences CsA pharmacokinetics. All patients had mild to moderate hypertension and received triple immunosuppressive therapy with CsA, azathioprine, and prednisolone. Throughout a 4-week period of isradipine treatment, blood CsA levels (specific and nonspecific monoclonal antibodies) remained stable. The mean trough specific level was 121 +/- 14 micrograms/L following placebo, compared to 120 +/- 14 micrograms/L during isradipine. Corresponding non-specific values were 465 +/- 68 and 474 +/- 63 micrograms/L. Also, values for Cmax, AUC, and t1/2 were not significantly changed following 4 weeks of isradipine. Mean arterial pressure was significantly reduced at the end of the study. This study implies that isradipine does not influence CsA metabolism. Further studies should be carried out to determine its long-term effects on CsA pharmacokinetics and renal function in transplanted patients.

The measurement of haloperidol and reduced haloperidol in neonatal hair as an index of placental transfer of maternal haloperidol.

Abstract: Hair samples were collected at time of delivery from three neonates and their schizophrenic mothers, who had been taking haloperidol (HP) during the perinatal period to control worsening psychotic symptoms. Maternal hair was cut into 1-cm lengths, and concentrations of HP and its major metabolite, reduced haloperidol (RHP), were measured by high-performance liquid chromatography. Neonatal hair was cut into halves, and the concentrations of HP and RHP in each half were measured. The distribution of both HP and RHP along the maternal hair paralleled the dosage of HP when hair growth was assumed to be 1 cm per month. In the upper half of hair from each of two neonates neither HP nor RHP was detected. Only HP was detected in the lower half from one, and a small peak of HP in the chromatogram was observed in the other, though under the detection limit. In the third neonate both HP and RHP were detected from both halves of hair, but the concentration of HP was larger in the lower half than in the upper. These findings suggest the possibility of monitoring the transfer of maternal HP through placenta by measuring HP and RHP concentrations in neonatal hair.

Measurement of phenytoin and carbamazepine in an ultrafiltrate of saliva.

Abstract: SummaryWe have introduced a method of collecting a prepurified sample of saliva in the mouth for the quantitative determination of phenytoin and carbamazepine. The patient places in the mouth an osmotic device that accumulates in >8 min a volume of ∼1.2 ml clear ultrafiltrate devoid of molecules > 1

Teicoplanin measurement in patients with renal failure: comparison of fluorescence polarization immunoassay, microbiological assay, and high-performance liquid chromatographic assay.

Abstract: Characterization of antibiotic pharmacokinetics in patients with renal insufficiency may be complicated by interfering substances within the assay. We compared three different assays for teicoplanin in serum and dialysate of 10 hemodialysis and six continuous ambulatory peritoneal dialysis (CAPD) patients. The microbiological assay (micro) had a within-run and between-run coefficient of variation (% CV) of less than 7.5% for concentrations ranging from 0.2 to 96 micrograms/ml. The high-performance liquid chromatographic assay (HPLC) within- and between-run %CV was less than 8% for concentrations ranging from 1 to 80 micrograms/ml. The fluorescence polarization immunoassay (FPIA) within- and between-run %CV was less than 7% for concentrations ranging from 5 to 100 micrograms/ml. In serum of hemodialysis patients FPIA results were slightly higher than HPLC results: FPIA = 1.11 HPLC + 2.37 (r = 0.975, n = 202), and FPIA concentrations in serum were also slightly higher than those measured by micro (FPIA = 1.21 micro - 1.57, r = 0.972, n = 161). The HPLC and micro serum results were also comparable in hemodialysis patients: micro = 0.92 HPLC + 2.89, r = 0.953, n = 160. However, in CAPD patients micro results were lower than HPLC results in serum (micro = 0.82 HPLC + 0.49, r = 0.981, n = 262). In peritoneal dialysate, HPLC values were approximately 60% of the micro values. Thus, FPIA may be the optimal technique for therapeutic monitoring of teicoplanin in the clinical setting due to its simplicity, specificity, and good correlation to HPLC and micro.

An improved high-performance liquid chromatographic method for the simultaneous measurement of halofantrine and desbutylhalofantrine in human serum.

Abstract: A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method, with ultraviolet detection, for simultaneous measurement of halofantrine (HAL) and desbutylhalofantrine (BHAL) in human serum is described. Sample preparation involved protein precipitation, followed by a solid-phase clean-up and a liquid-liquid extraction. Chromatographic separation was carried out on an Ultrasphere C8 column (25 cm x 4.6 mm I.D., 5 mu-m particle size) using a mobile phase of acetonitrile: water, 75:25, (vol/vol), with 0.2% (w/vol) sodium dodecyl sulfate and 0.2% (vol/vol) glacial acetic acid. The serum sample volume used was 0.5 ml, with concentrations normalized to 1 ml. Retention times for BHAL, HAL, and the internal standard were 5.5, 8.3, and 11.5 min, respectively, with a total run time of 13.5 min. The average extraction recovery for HAL was 85.6% and 100.5% for BHAL. Inter- and intra-assay precisions of HAL and BHAL were less-than-or-equal-to 7.5%, with an accuracy of less-than-or-equal-to 10.8% over three concentrations (0.02, 0.5, 2.0-mu-g/ml). Detection limits of HAL and BHAL were 5 and 3 ng/ml, respectively. The new HPLC method resulted in cleaner chromatograms and a 1.7-fold faster run time than previous HPLC methods. Application of the method with clinical specimens was demonstrated.

Monitoring serum levels of gentamicin to develop a new regimen for gentamicin dosage in newborns.

Abstract: The newborns studied had gestational ages ranging between 23-44 weeks, weights ranging between 725-4510 g, and were treated with standard doses of gentamicin (5.2 +/- 1.0 mg/kg/day). The gentamicin serum peak and trough levels were unrelated to administered doses, and a large proportion of patients had low (peak less than 4 micrograms/ml in 12%) or potentially toxic concentrations (trough greater than 2 micrograms/ml in 55%). The pharmacokinetic parameters (t1/2e, 8.2 +/- 4.8 h and Vd, 0.64 +/- 0.22 L/kg) varied markedly between patients. The newborn's weight, age, gestational age, and serum creatinine were factors of importance for the variability of gentamicin serum levels. The newborns were divided into four groups: gestational period less or more than 37 weeks and age below or above 7 days. These groups had different gentamicin serum levels and pharmacokinetic parameters. The results suggest that a gentamicin dosage regimen based on the division of newborn patients into subgroups or calculated from individual pharmacokinetic characteristics would decrease the risk of obtaining potentially toxic or subtherapeutic gentamicin concentrations after the use of standard doses.