Free Fraction Of Drug Research Articles

In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood.

The binding of CPT-11 and SN-38 to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. In plasma, CPT-11 was 66-60% bound in the range 100-4000 ng/ml and SN-38 was 94-96% bound in the range 50-200 ng/ml. At these concentrations the plasma binding of CPT-11 was slightly saturable, but the plasma binding of SN-38 was concentration-independent. Albumin was the main carrier of CPT-11 and SN-38 in plasma. In blood, the binding of CPT-11 was moderate (80%), mainly to plasma proteins (47%) and erythrocytes (33%). The binding of SN-38 was high (99%) and most of SN-38 in blood was located in blood cells (approximately 66%) The simulation of a grade 3 hematotoxicity (according to National Cancer Institute's Common Toxicity Criteria grading) on the SN-38 blood distribution yielded an increase in fu (free fraction of drug in plasma) from 1.05 to 2.08 and a decrease in C(Bl)/C(P) from 1.66 to 1.14 (both resulting from a decreased cell binding).

Measurements of maternal protein binding of bupivacaine throughout pregnancy.

Pregnancy-related decreases in protein binding may contribute to altered effects of local anesthetics in the parturient. Previous studies have measured protein binding of bupivacaine in term parturients; the current study defines the ratio of bound-to-free bupivacaine throughout gestation at both therapeutic and toxic systemic concentrations of bupivacaine. Venous samples were obtained from 81 women, including 70 parturients, ranging from 7 to 42 wk of gestation and 11 nonpregnant controls. The percent bound bupivacaine at a fixed concentration was determined for each sample at both therapeutic (1 microg/mL) and toxic (5 microg/mL) concentrations using an ultrafiltration technique. Albumin and alpha-1-glycoprotein levels were also measured. Linear regression analysis showed a significant increase in concentration of free bupivacaine throughout gestation at the 5-microg/mL concentration, corresponding to a decrease demonstrated in both albumin and alpha-1-glycoprotein levels. A similar correlation was not found at the 1-microg/mL concentration. Although the relative magnitude of these changes is small, the relative change in free drug throughout gestation is large. Protein binding is only one of several mechanisms that may influence the susceptibility to local anesthetic toxicity in the parturient; however, its relative importance remains unclear. When venous samples taken from pregnant women were mixed with 5 microg/ml bupivacaine and analyzed, an increase in the free fraction of drug was seen with increasing gestational age, corresponding to decreases in alpha-1-glycoprotein and albumin.

Measurements of Maternal Protein Binding of Bupivacaine Throughout Pregnancy

Pregnancy-related decreases in protein binding may contribute to altered effects of local anesthetics in the parturient. Previous studies have measured protein binding of bupivacaine in term parturients; the current study defines the ratio of bound-to-free bupivacaine throughout gestation at both therapeutic and toxic systemic concentrations of bupivacaine. Venous samples were obtained from 81 women, including 70 parturients, ranging from 7 to 42 wk of gestation and 11 nonpregnant controls. The percent bound bupivacaine at a fixed concentration was determined for each sample at both therapeutic (1 μg/mL) and toxic (5 μg/mL) concentrations using an ultrafiltration technique. Albumin and α-1-glycoprotein levels were also measured. Linear regression analysis showed a significant increase in concentration of free bupivacaine throughout gestation at the 5-μg/mL concentration, corresponding to a decrease demonstrated in both albumin and α-1-glycoprotein levels. A similar correlation was not found at the 1-μg/mL concentration. Although the relative magnitude of these changes is small, the relative change in free drug throughout gestation is large. Protein binding is only one of several mechanisms that may influence the susceptibility to local anesthetic toxicity in the parturient; however, its relative importance remains unclear. Implications When venous samples taken from pregnant women were mixed with 5 μg/ml bupivacaine and analyzed, an increase in the free fraction of drug was seen with increasing gestational age, corresponding to decreases in α-1-glycoprotein and albumin.

Dynamic dialysis for the drug release evaluation from doxorubicin–gelatin nanoparticle conjugates

The drug release from doxorubicin (DXR)–gelatin nanoparticle conjugates was evaluated by means of a dynamic dialysis technique. The study was carried out in absence and in presence of a proteolytic enzyme (trypsin) able to degrade the carrier. In a preliminary study the apparent permeability constant ( K cv) of the drug through the dialysis bag was evaluated in several media. On the basis of this screening, a saline solution (NaCl 0.9%, w/v) resulted appropriate to carry out the dialysis study since, in this medium, the K cv did not depend on the drug concentration in the donor solution. In absence of the enzyme only a little fraction (from 9 to 13%, w/w of the drug content) was released from nanoparticles. This fraction was considered as the evidence of the free drug fraction. After the addition of trypsin, the diffusion of a further drug fraction was observed. This fraction is probably due to a fraction of the DXR–peptide conjugates characterised by a molecular weight lower than membrane cut-off (3500 Da).

Standards of laboratory practice: cardiac drug monitoring

In this Standard of Laboratory Practice we recommend guidelines for therapeutic monitoring of cardiac drugs. Cardiac drugs are primarily used for treatment of angina, arrhythmias, and congestive heart failure. Digoxin, used in congestive heart failure, is widely prescribed and therapeutically monitored. Monitoring and use of antiarrhythmics such as disopyramide and lidocaine have been steadily declining. Immunoassay techniques are currently the most popular methods for measuring cardiac drugs. Several reasons make measurement of cardiac drugs in serum important: their narrow therapeutic index, similarity in clinical complications and presentation of under- and overmedicated patients, need for dosage adjustments, and confirmation of patient compliance. Monitoring may also be necessary in other circumstances, such as assessment of acetylator phenotypes. We present recommendations for measuring digoxin, quinidine, procainamide (and N-acetylprocainamide), lidocaine, and flecainide. We discuss guidelines for measuring unbound digoxin in the presence of an antidote (Fab fragments), for characterizing the impact of digoxin-like immunoreactive factor (DLIF) and other cross-reactants on immunoassays, and for moni-toring the unbound (free fraction) of drugs that bind to alpha1-acid glycoprotein. We also discuss logistic, clinical, hospital, and laboratory practice guidelines needed for implementation of a successful therapeutic drug monitoring service for cardiac drugs.

Effect of Altered Serum Lipid Concentrations on the IC50 of Halofantrine against Plasmodium Falciparum

□ Halofantrine (Hf) is a highly lipophilic antimalarial which significantly associates with triglyceride (TG) rich plasma lipoproteins, and this is likely manifest as a decrease in the free fraction of drug. This study assessed the effect of using growth media containing 10% serum containing different concentrations of TG (i.e. TG-rich plasma lipoproteins) on the IC50 of Hf determined using continuous in vitro culture of Plasmodium falciparum. Serum was collected from a human subject in either a fasted state or at various times after ingestion of a fatty meal. There was a linear and statistically significant 2.5-fold increase in the IC50 of Hf across a 6-fold range of increasing TG concentrations, with the increased IC50 values being ascribed to a decreased free fraction of Hf in the growth media due to sequestration by TG-rich lipoproteins. Chloroquine diphosphate, which is hydrophilic and not significantly bound by TG-rich lipoproteins, was used as a control and its IC50 values were independent of TG concentrations. These data indicate that consideration should be given to the adoption of standard conditions for the collection of serum with respect to pre-or postprandial states, and that subject- and disease-related factors which alter plasma lipoprotein profiles should be considered when interpreting the IC50 profile of Hf (and possibly other lipophilic antimalarials). Furthermore, although food is known to affect the pharmacokinetics of Hf, these data suggest that altered plasma lipoprotein profiles could also influence its pharmacodynamic profile.

Pharmacokinetic changes during pregnancy and their clinical relevance.

The dynamic physiological changes that occur in the maternal-placental-fetal unit during pregnancy influence the pharmacokinetic processes of drug absorption, distribution and elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal function and hence drug absorption rates. Ventilatory changes may influence the pulmonary absorption of inhaled drugs. As the glomerular filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced, whereas hepatic drug metabolism may increase, decrease or remain unchanged. A mean increase of 8 L in total body water alters drug distribution and results in decreased peak serum concentrations of many drugs. Decreased steady-state concentrations have been documented for many agents as a result of their increased clearance. Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotransformation or renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug concentration is responsible for drug effects, the above mentioned changes are probably of no clinical relevance. The placental and fetal capacity to metabolise drugs together with physiological factors, such as differences acid-base equilibrium of the mother versus the fetus, determine the fetal exposure to the drugs taken by the mother. As most drugs are excreted into the milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma. The milk to plasma (M:P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs the amount ingested by the infant rarely attains therapeutic levels.

Estrogen-induced changes in protein binding of bupivacaine during in vitro fertilization.

Patients having in vitro fertilization (IVF) procedures that use gonadotropin-releasing hormone agonist down-regulation undergo hormonal manipulation of estrogen concentrations to induce oocyte maturation. After achieving minimal estrogen concentrations (baseline), stimulation increases estrogen concentrations to supraphysiologic levels, leading to egg retrieval. The isolated effect of estrogen on protein binding has not previously been reported. This study was conducted to measure the effect of estrogen concentrations on protein binding of two concentrations of bupivacaine, 1 microg/ml and 5 microg/ml, corresponding, respectively, to systemic concentrations expected after administration of epidural anesthesia and associated with bupivacaine toxicity. Serum proteins were measured to address the mechanism. Twenty-nine healthy women undergoing IVF procedures were enrolled and venous samples were drawn at times of minimal and maximal estrogen concentrations. The percentage of free bupivacaine was determined at fixed concentrations of 1 and 5 microg/ml. Serum albumin and alpha1-acid glycoprotein concentrations were measured at baseline and at retrieval in a group of 24 women. The percentage of free bupivacaine increased between times of minimal and maximal serum estrogen concentrations, corresponding to decreased protein binding. Concentrations of serum albumin and alpha1-acid glycoprotein decreased between baseline and retrieval times. Patients undergoing IVF procedures demonstrate a decrease in protein binding of bupivacaine from baseline concentrations. These changes may be explained by a decrease in albumin and alpha1-acid glycoprotein. During anesthesia for egg retrieval, clinicians should consider the implications of increased free fraction of drug, especially for highly protein-bound agents.

In vitro Binding of MX2 (KRN8602) and Epirubicin to Human Plasma Protein

This study compares the human plasma protein binding characteristics of MX2 and epirubicin. The binding characteristics were determined by equilibrium dialysis at various concentrations of the drugs. The binding dissociation constant (Kd), binding capacity (Bmax) and partitioning constant (Kp) were obtained by Scatchard analysis of the free and bound drugs in the dialysis compartments. Our results have demonstrated that plasma protein binds epirubicin or MX2 in an unsaturable appearance over the concentration up to 150 mumol/l. At the same concentrations, plasma protein binds more epirubicin than MX2. The nature of the interaction may consist of two classes of specific binding, and a partitioning. The binding dissociation constants were 18 and 17.5 mumol/l for the higher binding class (Kd1) and 315.8 and 316.9 mumol/l for the lower binding class (Kd2), respectively, for epirubicin and MX2. The respective maximum binding capacities (Bmax) of plasma protein for epirubicin and MX2 were significantly different, 0.045 and 0.029 mumol/g protein for the higher binding class (Bmax1), and 0.39 and 0.29 mumol/g protein for the lower binding class (Bmax2). The partitioning constants (Kp) were 21.5 x 10(-5) and 20 x 10(-5) litres/g protein for epirubicin and MX2, respectively. The results suggest that plasma protein binds epirubicin or MX2 with a similar affinity, but has less binding sites for MX2. One contributing mechanism to the difference in activity noted between epirubicin and MX2 may be changes in free drug fractions.

Blood-to-brain transfer of various oxicams: effects of plasma binding on their brain delivery.

The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-l-acid glycoprotein (AAG) solutions at various concentrations. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction. Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.

Determination of Free and Liposome-Associated Doxorubicin and Vincristine Levels in Plasma under Equilibrium Conditions Employing Ultrafiltration Techniques

A thorough understanding of the pharmacodynamic relationships associated with toxicity and efficacy behavior of liposome-encapsulated anticancer agents such as doxorubicin and vincristine will rely on the ability to accurately separate and quantify the free and liposome-associated drug fractions in plasma after administration. We have investigated the use of ultrafiltration as a method of isolating free doxorubicin and vincristine from liposomal drug under equilibrium conditions and compared it to previously developed nonequilibrium procedures based on solid-phase extraction. Adsorption of drugs dissolved in saline to the ultrafiltration devices resulted in concentration-dependent ultrafiltrate drug recoveries ranging from 41 to 96%. However, concentration-independent quantitative recovery of vincristine in saline solutions could be obtained by passivating the ultrafiltration devices with PEG-8000 and device drug adsorption was ameliorated for both agents by plasma. The ultrafiltration method provided a more reliable separation of free and protein-bound drug, whereas solid-phase extraction yielded artificially high free drug concentrations due to process-induced protein-bound drug complex dissocation. Also, coelution of liposomes with the free drug fraction using solid-phase extraction was 64- to 418-fold higher than observed with ultrafiltration. Taken together, these properties indicated a significantly increased degree of accuracy in measuring the amount of free doxorubicin and vincristine in samples containing liposomal formulations employing ultrafiltration compared to solid-phase extraction. The importance of this improvement was highlighted by observations that determinations of free drug concentrations in the plasma of mice injected with liposomal doxorubicin and vincristine were 3- to 12-fold higher using solid-phase extraction compared to ultrafiltration. Finally, the ultrafiltration procedure is rapid, versatile, and can be used for a wide range of drug and liposome concentrations and free drug/liposomal drug ratios.

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. 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 tha the theoretically recommended factor of 20. 2. 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. 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. 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. 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.

The effect of lipophilicity on the protein binding and blood cell uptake of some acidic drugs

Quantitative relationships between lipophilicity (characterized by the octanol-water partition coefficient) and binding to both human plasma proteins and blood cells have been studied in a group of model anionic drugs (benzoic and phenylacetic acid derivatives). Protein binding in plasma and accumulation in blood cells in suspension increases with increasing lipophilicity. For quantitative evaluation, the equation log R = a + b log D has been employed, where R is the bound-to-free drug ratio, D is lipophilicity, and a and b are constants. Whereas the protein bound-to-free drug ratio is proportional to drug lipophilicity, the cell bound-to-free drug ratio correlates with lipophilicity to the power 0.685. Distribution in whole blood is affected by protein binding and also by cell accumulation. In blood, the free drug fraction and the fraction in blood cells decrease with increasing lipophilicity, whereas the protein-bound fraction correspondingly increases.

Binding of a new multidrug resistance modulator, S9788, to human plasma proteins and erythrocytes.

The interactions of S9788 with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows an estimation of the plasma proteins and erythrocytes binding parameters. S9788 was 98% bound to plasma and blood. Lipoproteins bound S9788 with high affinities (binding constants of 0.645, 12.8 and 87.0 x 10(6) M-1 for HDL, LDL and VLDL, respectively) and accounted for more than 55% of the total circulating S9788. Albumin and alpha 1-acid glycoprotein also bound S9788 with lower binding constants of 0.022 and 0.245 x 10(6) M-1. S9788 was mainly distributed in the plasma blood compartment (75-80%) with blood-to-plasma concentrations ratio of 0.6 to 0.7. These results indicate that, in vivo, the fraction of blood S9788 available for tissue diffusion, i.e., the free drug fraction in blood, should depend on lipoprotein concentration in plasma.

Microdialysis sampling to determine the pharmacokinetics of unbound SDZ ICM 567 in blood and brain in awake, freely-moving rats.

The free concentrations of the serotoninergic 5-HT3 antagonist SDZ ICM 567 in blood and in the central nervous system were examined in awake, freely-moving rats using blood and brain microdialysis coupled to liquid chromatography. Microdialysis probes were implanted in the jugular vein and in the frontal cortex and dialysis samples were simultaneously collected from both sites. Pharmacokinetic parameters were calculated after a 10 mg/kg intravenous dose of [14C]SDZ ICM 567. The elimination half lives measured in whole blood, brain and blood microdialysates were similar (congruent to 1.7 h). The AUC0-5h corresponding to the unbound drug was 462 +/- 142 ng.ml-1.h in blood dialysate, not significantly different from the AUC corresponding to the free concentration in whole blood, i.e. 586 +/- 63 ng.ml-1.h. The free fraction in blood obtained in vitro by equilibrium dialysis (21%) or by microdialysis (19%) was not statistically different from that obtained in vivo (17%) in microdialysis experiments. The unbound concentrations (AUC0-5h) of SDZ ICM 567 in the brain cortex were 86 +/- 24 ng.ml-1.h, lower than those expected from unbound blood concentrations, suggesting an active transport out of the central nervous system. Finally, microdialysis sampling allowed the determination of pharmacokinetic parameters of SDZ ICM 567 in blood and brain as well as the estimation of the free fraction of drug in blood.

Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges

Physicochemical properties of drugs were related to their ability to enter the cerebrospinal fluid (CSF) in humans by reevaluation of previously reported studies. Either the quotients of the drug concentrations in CSF and serum at steady state ( C CSFss C Sss ) or, since in most cases CSF passage was studied after a short-term infusion, the ratios of the areas under th concentration-time curves in CSF and serum ( AUC CSF AUC S ) were taken as measures of CSF passage. AUC S and C Sss] were corrected for binding to serum proteins (AUC Sf, C Sssf). Of the drugs studied the quotient of the octanol/water partition coefficient at pH 7.4 (PC) as a measure of lipophilicity and the square root of the molecular weight ( MW 1 2 ) correlated with AUC CSF AUC S (Spearman's rank correlation coefficient r S = 0.78, P < 0.01) and with AUC CSF AUC Sf ( r S = 0.90, P < 0.01). PC · MW −1 2 was related to AUC CSF AUC Sf (or C CSFss C Sssf , respectively) by the equation: AUC CSF AUC Sf = 0.96 + 0.091 · ln( PC · MW −1 2 ) . For 0.0001 ≤ PC · MW −1 2 ≤ 1.0 this function may be of value for the pr humans when the physicochemical properties of a drug are known and when active transport or metabolism are negligible.

Etoposide dosage and pharmacodynamics

Etoposide is a schedule-dependent cytotoxic drug with high single agent activity in small-cell lung cancer and lymphoma. Despite its clear dose-dependent myelosuppressive activity, dose-dependent evidence of its anti-tumour activity is harder to demonstrate. A number of reports have correlated haematological toxicity with pharmacokinetic and physiological parameters, which explains some of the variability in dynamic effects that exists between patients. Recent reports have also suggested that anti-tumour response may be related to plasma etoposide concentration. In our own studies we have investigated factors that influence the pharmacodynamic effects of etoposide, principally with regard to haematological toxicity, and these studies have highlighted a number of patient groups who are at risk. Impaired renal function causes a reduction in clearance of etoposide, resulting in increased systemic exposure and more profound myelotoxicity. A 30% dose reduction in this group is recommended to normalise the area under the plasma concentration-time curve (AUC). Patients with low serum albumin concentrations (< 35 g/l) also showed significantly worse haematological toxicity, but with no apparent change in total drug pharmacokinetics. There was, however, an increase in the free drug fraction in this group due to decreased protein binding, such that the free drug AUC was similar to that found in patients with renal dysfunction. This would also indicate that a dose reduction of around 30%-40% is required in this patient group. Patients with normal albumin levels but liver enzyme values (aspartate transaminase or gamma-glutamyl transpeptidase) more than 3 times the upper limit of normal also had a less marked but significant increase in neutropenia. In patients with normal organ function, age was the only significant factor in predicting the degree of leukopenia/neutropenia, and increasing age was also associated with decreasing drug clearance and an increase in drug AUC. A small dose reduction and/or careful monitoring is required in this patient group. Further studies are required to elucidate further the relationship between the pharmacokinetics of etoposide and its pharmacodynamics, particularly with regard to anti-tumor activity, and to determine the role of individualised therapy, based on a pharmacokinetic parameter, in reducing the dynamic variability and optimising the use of this drug.

Articular Pharmacokinetics of Protein-Bound Antirheumatic Agents

By what mechanism do nonsteroidal anti-inflammatory drugs (NSAIDs) move from plasma into synovial fluid and back, and how does binding to plasma albumin in vitro relate to articular transport in vivo? To evaluate these issues, concurrent plasma and synovial fluid data of 8 different NSAIDs from 10 single-dose trials were analysed by a simple compartmental model incorporating intra-articular volume, synovial plasma flow rates and protein transport. All pharmacological and physiological data were taken from published studies of chronic knee effusions in patients with rheumatoid arthritis. The analysis shows that these protein-bound NSAIDs readily leave the vasculature and enter synovial fluid during each transit of synovial microvessels. The mean rate of transport, 0.23 min-1, is consistent with passive diffusion at rates far in excess of those attributable to movement of albumin-bound drug or of the small, free-drug fraction found by equilibrium dialysis. These findings are explained by association and dissociation of NSAIDs and albumin that occur far more rapidly than vascular transit. Ongoing dissociation makes bound drug available for transvascular exchange and thereby diminishes the pharmacokinetic significance of binding data obtained in vitro.

Saliva testing for drugs of abuse.

Saliva testing for drugs of abuse can provide both qualitative and quantitative information on the drug status of an individual undergoing testing. Self-administration by the oral, intranasal, and smoking routes often produces "shallow depots" of drug that contaminate the oral cavity. This depot produces elevated drug concentrations that can be detected for several hours. Thereafter, saliva drug concentrations generally reflect the free fraction of drug in blood. Also, many drugs are weak bases and saliva concentrations may be highly dependent upon pH conditions. These factors lead to highly variable S/P ratios for many of the drugs of abuse. Table 3 provides a compilation of experimental and theoretical S/P (total) ratios determined for drugs of abuse. Estimations of the theoretical S/P (total) ratios for acidic and basic drugs were based on the Henderson-Hasselbalch equation. Saliva pH was assumed to be 6.8 unless reported otherwise by the investigators. Generally, there was a high correlation of saliva drug concentrations with plasma, especially when oral contamination was eliminated. Assay methodology varied considerably, indicating that saliva assays could be readily developed from existing methodology. There are many potential applications for saliva testing for drugs of abuse. Table 4 lists several general areas in which information from saliva testing would be useful. Clearly, saliva drug tests can reveal the presence of a pharmacologically active drug in an individual at the time of testing. Significant correlations have been found between saliva concentrations of drugs of abuse and behavioral and physiological effects. Results indicate that saliva testing can provide valuable information in diagnostics, treatment, and forensic investigations of individuals suspected of drug abuse. It is expected that saliva testing for drugs of abuse will develop over the next decade into a mature science with substantial new applications.

Decreased protein binding of alfentanil in plasma from children with kidney or liver failure

SummaryDisease states, including end‐stage kidney or liver failure, can alter the protein binding of various drugs in children. The plasma protein binding of alfentanil was evaluated in blood samples from 15 children about to undergo kidney transplantation, 21 children undergoing liver transplantation, and 28 otherwise healthy children undergoing elective surgery. Compared with the healthy children, patients with kidney disease had a significant decrease in protein binding (89.2%± 5.4 v. 93.1%± 3.2), an increase in α1‐acid glycoprotein concentration (108.8 mg·dl−1± 44.3 v. 71.8 mg·dl−1± 30.7), and no change in albumin concentration (3910 mg·dl−1± 754 v. 4555 mg·dl−1± 524); whereas patients with liver disease had a significant decrease in protein binding (85.9%± 6.2 v. 93.1%± 3.2), no change in α1‐acid glycoprotein concentration (65.8 mg·dl−1± 31.8 v. 71.8 mg·dl ± 30.7), and a decrease in albumin concentration (3045 mg·dl−1± 1255 v. 4555 mg·dl−1± 524). Because alfentanil is highly protein bound, even small changes in the drug's free fraction could have marked pharmacodynamic effects in patients with kidney or liver failure.