John R. Briggs

The Binding of Selected Therapeutic Drugs to Human Serum α-1 Acid Glycoprotein and to Human Serum Albumin In Vitro

The binding of acetaminophen, lidocaine, phenobarbital, phenytoin, theophylline, and valproic acid to human serum &agr;-1 acid glycoprotein (orosomucoid) and to human serum albumin separately in vitro was investigated using equilibrium dialysis of the unlabeled drugs. Each drug was studied at a therapeutic concentration. Alpha-1 acid glycoprotein was studied at one elevated and two physiological concentrations, whereas albumin was studied at one physiological and two low concentrations. The nonphysiological concentrations were consistent with those that might be seen in a variety of clinical conditions. Acetaminophen, phenobarbital, theophylline, and valproic acid showed negligible binding to &agr;-1 acid glycoprotein. However, lidocaine and phenytoin demonstrated binding to this protein, and increases in the &agr;-1 acid glycoprotein concentration produced decreases in the unbound (free) or “active” concentration of these two drugs. All drugs but acetaminophen bound to albumin, and decreases in the albumin concentration yielded increases in the unbound (free) or “active” concentration of the remaining 5 drugs. These findings are significant when lidocaine, phenytoin, phenobarbital, theophylline, or valproic acid are used in patients with clinical conditions that may affect the concentration of these two binding proteins.

Carisoprodol An Unrecognized Drug of Abuse

During a 6-month monitoring period, carisoprodol was detected in the urine specimens of 19 patients for whom drug screening had been ordered for purposes of patient care. The clinical history suggested that in 7 cases the drug was abused or implicated in a suicide attempt or gesture. In another 7 cases, the drug was used primarily for medical purposes, and in 5 cases the reason for use could not be determined. One patient ingested homemade tablets that were found to contain carisoprodol. In an additional case, the drug was detected in breast milk. Physical findings, clinical history, and treatment are described, and the profile of a typical carisoprodol user is discussed. It seems that carisoprodol has become an unrecognized drug of abuse, at least in our community. This drug and its metabolite, meprobamate, should be included in comprehensive drug screening.

Stability of drug concentrations in plasma stored in serum separator blood collection tubes

The stability of therapeutic concentrations of 11 drugs (amikacin, carbamazepine, digoxin, gentamicin, lithium, methotrexate, phenobarbital, phenytoin, quinidine, theophylline, tobramycin) and two trace elements (copper and zinc) in plasma stored in serum separator (“Corvac” brand) blood collection tubes was investigated over a 1 week period of storage in the refrigerator. No significant change in concentration was noted for any analyte during the study period. Concentrations were also not significantly different from those observed during concurrent storage of the same plasma samples in non-serum separator (“Vacutainer” brand) blood collection tubes.

The effect of parenteral nutrition fluids on the binding of therapeutic drugs to human serum in vitro.

The competitive binding of seven therapeutic drugs (carbamazepine, phenytoin, phenobarbital, procainamide, quinidine, theophylline, and valproic acid) to human serum and to five commonly used parenteral nutrition fluids in vitro was studied using equilibrium dialysis. For five of the drugs, all parenteral nutrition fluids bound less drug than human serum—phenobarbital (up to 14% less), phenytoin (up to 46% less), procainamide (up to 43% less), quinidine (up to 25% less), and valproic acid (up to 77% less)—suggesting that the presence of these fluids might increase the free fraction of these drugs in vivo. For carbamazepine, the fluids bound up to 82% more drug, suggesting that the presence of these fluids might decrease the free fraction of this drug in vivo. For theophylline, the fluids produced a minimal (no more than 5%) effect on binding to serum. The administration of parenteral nutrition fluids may significantly alter the free (active) fraction of some therapeutic drugs.

Valproic acid binding to human serum and human placenta in vitro.

The binding characteristics of the antiepileptic agent and teratogen valproic acid for human serum and human placenta were investigated utilizing equilibrium dialysis of the drugs in serum and in homogenates of whole placenta so that the transplacental transfer of the drug could be better defined. A low-capacity, high-affinity binder and a high-capacity, low-affinity binder for valproic acid were found in serum. However, there was only minimal, nonspecific binding of the drug to placenta. It appears that transplacental transfer of valproic acid is not mediated by binding to placenta. It is likely that such transfer occurs by passive diffusion, which may be facilitated by the lipophilicity of the drug and by development of a pH gradient across the placenta. These findings indicate that the placenta is not a depot for valproic acid.

The effect of ethanol and pH on the adsorption of drugs from simulated gastric fluid onto activated charcoal

The effect of ethanol and pH on the adsorption of acetaminophen (ACET), phenobarbital (PHB), phenytoin (PHY), salicylic acid (SA), and theophylline (THEO) from simulated gastric fluid onto activated charcoal was studied. For the ethanol study, each drug was prepared at a concentration of 10 g/L in ethanol; in hydrochloric acid (HCl), 1.2 mol/L; and in HCl, 1.2 mol/L, containing 75% ethanol, 50% ethanol, and 25% ethanol (v/v), respectively. For the pH study, each drug was prepared at a concentration of 10 g/L in HCl, 1.2 mol/L, pH 1.0, and in buffers of pH 1.7, 3.0, 4.0, 4.8, 5.8, 6.5, 7.4, and 9.4. After the addition of 1 g of activated charcoal to 10 mL of each solution, it was incubated for one hour at 37 °C. For comparison, in each experiment a blank consisting of the solution without charcoal was also incubated. With increasing concentrations of ethanol, there were substantial decreases in the adsorption of ACET, PHB, and PHY to charcoal. Ethanol-induced decreases in the adsorption of SA and THEO were less pronounced. Changes in pH did not affect the adsorption of ACET, PHB, PHY, or THEO. However, the adsorption of SA was decreased slightly at pH 1.0 and 3.0.

Tissue Distribution of Methadone Following Percutaneous Absorption in Vivo

AbstractUsing the intact hairless mouse as an experimental model for human skin, the relative distribution of methadone in blood, brain, heart, liver, and lung was studied hourly for 4 hr following percutaneous absorption of the hydrochloride salt in aqueous solution. The resulting tissue distribution was compared with that observed following administration of the drug by intraperitoneal injection. With percutaneous absorption the mean tissue concentrations of methadone generally increased with time, presumably due to sustained administration of the compound. Blood concentrations were similar to those observed after oral administration of pharmacologic doses of methadone to humans. By 4 hr the mean methadone concentration in blood was higher with percutaneous absorption than with intraperitoneal injection. However, in all other instances mean tissue concentrations for each hour were higher following intraperitoneal injection of methadone. Per cutaneous absorption may prove to be a potentially effective ro...

Studies of the Inhibition of Serum Pseudocholinesterase Activity In Vitro by Commonly Used Drugs

We studied the effect of 17 commonly used drugs, including prescription and over-the-counter medications, on the activity of serum pseudocholinesterase (PCE) in vitro. Normal pooled human serum was incubated for 120 minutes at 37 degrees C with therapeutic serum concentrations of prescription and over-the-counter drugs, and the postincubation PCE activity was measured. Morphine, quinidine, and thioridazine depressed PCE activity by more than 5% while no or negligible effect was noted following incubation with acetaminophen, chlordiazepoxide, chlorpromazine, desipramine, doxepin, imipramine, methamphetamine, nortriptyline, phenobarbital, phenytoin, procainamide, salicylic acid, theophylline, and valproic acid. Depression of PCE activity can prolong the half-life of coadministered agents with metabolism mediated by PCE.

PERCUTANEOUS ABSORPTION OF METHOTREXATE AS ITS SODIUM SALT IN VIVO

AbstractThe percutaneous absorption of methotrexate as its sodium salt has been demonstrated in vivo using the hairless mouse as an experimental model. Following topical administration of 0.2 mg sodium methotrexate in concentrated aqueous solution, drug concentrations were measured in plasma at 3, 4, 5, 6, and 8 hrs. Methotrexate was not detected in plasma at 3 hrs, but it was found in pharmacologically significant mean concentrations for the remainder of the study (/μmol/L): 4 hrs, 0.13; 5 hrs, 0.38; 6 hrs, 1.01; and 8 hrs, 0.23. These findings suggest that percutaneous absorption of methotrexate does occur and that individuals handling the drug should take appropriate precautions. Biological monitoring may also be indicated for such persons.

Effect of parenterally administered atropine on the percutaneous absorption of phencyclidine and methadone

The effect of parenterally administered atropine on the previously demonstrated percutaneous absorption of phencyclidine and methadone was investigated in vivo using the hairless (SKH, hr-1/hr-1) mouse as an experimental model. At both three hours and four hours following topical application of aqueous phencyclidine hydrochloride, the mean drug concentration in liver was significantly lower in mice that had received atropine sulfate by intraperitoneal injection than in mice that had received only water by this route (3 hrs: p less than 0.01; 4 hrs: p less than 0.02). Prior to three hours no statistically significant difference was noted. In contrast, parenteral administration of atropine produced no significant effect upon the percutaneous absorption of aqueous methadone hydrochloride over a four-hour period. Atropine inhibition of absorption is likely due to cutaneous dehydration, and it may be drug-specific and/or dose-related. These findings are correlated with the previously reported ethanol inhibition of percutaneous absorption. The therapeutic implications of these observations are discussed.