Mack R. Holdiness

Clinical Pharmacokinetics of N-Acetylcysteine

SummaryN-Acetylcysteine is useful as a mucolytic agent for treatment of chronic bronchitis and other pulmonary diseases complicated by the production of viscous mucus. It is also used as an antidote to paracetamol (acetaminophen) poisoning and found to be effective for the prevention of car-diotoxicity by doxorubicin and hae norrhagic cystitis from oxazaphosphorines.After an oral dose of N-acetylcysteine 200 to 400mg the peak plasma concentration of 0.35 to 4 mg/L is achieved within 1 to 2 hours. Although the data are conflicting, it appears that the administration of charcoal may interfere with drug absorption, with up to 96% of the drug adsorbed on to the charcoal. Information on absorption in the presence of food or other drugs is not available. The volume of distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant, reaching approximately 50% 4 hours after the dose. Pharmacokinetic information is not available as to whether or not N-acetylcysteine crosses the blood-brain barrier or placenta, or into breast milk. Renal clearance has been reponed as 0.190 to 0.211 L/h/ke and approximately 70% of the total body clearance is nonrenal. Following oral administration, reduced /V-acetyl-cysteine has a terminal half-life of 6.25h. Little is known of the metabolism of this agent, although it is believed to be rapidly metabolised and incorporated on to proteins. The major excretory product is inorganic sulphate.Frequently reported side effects are nausea, vomiting and diarrhoea. Biochemical and hae-matological adverse effects are observed but are not clinically relevant. Drug interactions of clinical significance have been observed with paracetamol, glutathione and anticancer agents.

Clinical Pharmacokinetics of the Antituberculosis Drugs

SummaryThe quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable ‘first-pass’ effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid.With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug’s antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide.The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group. The elimination half-life of kanamycin increases from 107 minutes in younger individuals to 282 minutes in elderly populations.Recent data indicate that isoniazid, rifampicin, ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin and cycloserine appear in measurable quantities in breast milk, with isoniazid having the highest recorded level of 2.3% of a daily administered dose.Pharmacokinetic drug interactions and techniques for therapeutic drug monitoring of each of these agents (and some of their metabolites) are also briefly reviewed. Consideration of the pharmacokinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.

Clinical pharmacokinetics of clofazimine. A review.

SummaryClofazimine is useful in the treatment of Hansen’s disease (leprosy) and some dermatological disorders, and is currently being used in drug regimens for patients with human immunodeficiency viral infections who are also infected with Mycobacterium avium complex.After an oral dose, absorption is variable, but when given in an oil-wax suspension is approximately 70%. Administration with food appears to increase the peak plasma drug concentration and reduce the time to peak level. Data on the volume of distribution and percentage or type of protein binding are not available; however, the drug undergoes extensive tissue distribution. Clofazimine does not cross the blood-brain barrier, but does cross the placenta, and is found in human breast milk.To date 3 urinary metabolites have been identified in man, but their biological activity is unknown. A substantial portion of the unchanged drug is excreted in faeces. The elimination half life is variable, with values as long as 70 days being quoted in the literature.Frequently reported side effects of clofazimine are hyperpigmentation of the skin and conjunctiva, and abdominal pain. These resolve upon cessation of therapy. Biochemical and haematological adverse effects have been reported, but are generally not clinically relevant. Pharmacokinetic drug interactions of potential clinical significance have been observed with dapsone, oestrogen, rifampicin and vitamin A.

Chromatographic analysis of antituberculosis drugs in biological samples

Numerous chromatographic and non-chromatographic methods of analysis for anti-tuberculosis drugs and metabolites in biological tissues have been discussed in this review. Depending upon the analytical methodology selected, limits of detection range from microgram to picogram levels. A number of examples have been given of the correlation between different types of assay procedures. The metabolism and pharmacokinetics have been described along with some of the commonly associated problems of sample collection and storage.

High-performance liquid chromatographic determination of N-acetylcysteine in human serum following acetaminophen overdosage

An analytical method has been developed for the determination of N-acetylcysteine in human serum following acetaminophen overdosage in humans. Serum samples were treated with dithiothreitol and the protein-freed product was derivatized with 2,4-dinitrofluorobenzene. N-Acetylhomocysteine thiolactone was used as an internal standard. Following diethyl ether extraction, the components were separated on a reversed-phase column with retention times of 7.4 and 9.9 min for N-acetylcysteine and internal standard, respectively. Ultraviolet detection at 365 nm was employed and little interference was noted from other serum components. The method has been applied to quantitation of N-acetylcysteine given as treatment for acetaminophen intoxication.

High Pressure Liquid Chromatographic Determination of Isoniazid and Acetylisoniazid in Human Plasma

Abstract A quantitative high pressure liquid chromatographic (HPLC) assay has been developed for the determination of isoniazid (INH) and acetylisoniazid (ACINH) in human plasma. Plasma samples were taken from a patient after oral administration of INH (with proven tuberculosis infection). A C18 reversed phase radial compression column was used to separate INH and ACINH from other plasma components. The analysis takes 10 minutes per sample and the lower limit of detection for each compound is 0.10 ug/ml plasma.

Transplacental Pharmacokinetics of the Antituberculosis Drugs

Information concerning passage of the antituberculosis drugs across the human placenta is sparse and scattered throughout the medical literature. Little mention was made of this subject in recent reviews of the clinical pharmacokinetics of these agents (Holdiness 1984, 1985a). However, a detailed survey indicates 6 of the 12 compounds commonly used have documented transplacental passage in humans (table I). If pregnancy occurs during the treatment of tuberculosis, the risk to the developing fetus must be considered in advising the expectant mother and her obstetrician. The indications for chemotherapy and the basic principles of management of the pregnant women with active tuberculosis are essentially no different from those in the non-pregnant patient (Snider 1984). Therapy with 2 drugs is instituted at standard doses, and the duration of treatment should not be altered by the patients pregnancy. Retrospective studies by Snider et al. (1980) have revealed a reasonable margin of safety for isoniazid, rifampicin, and ethambutol when utilised during pregnancy; questionable results have precluded the administration of streptomycin. From their research of the literature, these authors showed that 94% of all gestations terminated in delivery of apparently normal term infants. In utero exposure of fetuses to antituberculosis therapy revealed 2.8% with classified birth defects. It was suggested that with the exception of women on streptomycin, the risk of adverse gestational outcomes is no greater among pregnant women on antituberculosis regimens than among healthy pregnant females. Caution must be exercised when considering the teratogenic effects of these drugs as spontaneous abortions, stillbirths, birth defects and prematurity are common even in normal pregnancy. The possible teratogenic effects of this class of antibiotics in animal models and humans have recently been reviewed (Holdiness 1987a) and the reader is referred to this article. Snider (1984) indicated that preventive therapy should be given during the second and third trimesters of pregnancy to selected patients at high risk of development of progressive disease. Treatment should be instituted promptly when a tuberculous infection is detected. Preferred regimens are isoniazid-ethambutol, isoniazid-rifampicin, or isoniazid-ethambutol-rifampicin, although other drugs may be needed if the disease is recurrent or if there is resistance to these primary drugs.

Determination of Glutamic Acid Decarboxylase Activity in Subregions of Rat Brain by High Pressure Liquid Chromatography

Abstract A quantitative high pressure liquid chromato-graphic (HPLC) assay has been developed for the determination of glutamic acid decarboxylase (GAD) activity in subregions of rat brain. GAD activity was determined indirectly by measurement of gamma-aminobutyric acid (GABA). Fluorimetric detection was made possible by derivatization with ortho-phthalaldehyde and the limit of detection was 11 ng GABA.

A Simple Zone Melting Apparatus For Refining Organic Compounds

Abstract A simple zone melting apparatus has been constructed for purification of low melting [<230°C] organic compounds. Six hydrocarbons were doped with benzo[e]pyrene and the purity of the refining process was monitored by high pressure liquid chromatography. In all cases presented the purity achieved was greater than one part per billion.

A Comparison Of Measurement of Homovanillic Acid in Brain Tissue by Gas Chromatography Mass Spectrometry and Liquid Chromatography with Electrochemical Detection

Abstract A comparison of liquid chromatography with electrochemical detection (LCEC) and gas chromatography mass spectrometry (GCMS) has been made for analysis of homovanillic acid (HVA) in rat brain tissue. The LCEC procedure gave slightly higher average values of HVA in the samples measured; however, the HVA content determined by both methods related significantly. Rat brain meostriatum was used as representative samples for comparison of the two analytical procedures.