Prediction of Xenobiotic Metabolism by Non‐Invasive Methods

Loft, Steffen; Poulsen, Henrik E.

doi:10.1111/j.1600-0773.1990.tb00793.x

Cited by 13 publications

(6 citation statements)

References 82 publications

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“…These CYP isozymes are responsible in part for metabolism of as many as 70% of hepatic metabolized drugs. Several studies have evaluated the use of antipyrine in saliva to study metabolic function 137–139,141–144 …”

Section: Special Applications Of Salivary Drug Levelsmentioning

confidence: 99%

“…Several studies have evaluated the use of antipyrine in saliva to study metabolic function. [137][138][139][141][142][143][144] While antipyrine has been extensively used as a probe of overall hepatic CYP metabolism, there are limitations to its use, including a lack of metabolism by other important CYP enzymes including CYP2D6. 35,145 More importantly, because antipyrine is metabolized by multiple CYP isozymes, it is not necessarily possible to directly extrapolate metabolism of antipyrine to metabolism of a therapeutic agent that is metabolized by specific CYP.…”

Section: Special Applications Of Salivary Drug Levelsmentioning

confidence: 99%

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The Use of Oral Fluid for Therapeutic Drug Management

Langman

2007

Annals of the New York Academy of Sciences

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One of the underlying tenets of clinical pharmacology is that only free drugs are pharmacologically active. It is thought that only free drugs can cross biological membranes to interact with a given receptor to alter its function, and that drug responses, both efficacious and toxic, are a function of unbound concentrations. The rationale for measuring drugs in oral fluid is that the free fraction of a drug in plasma reaches equilibrium with the drug in saliva. Although reports concerning the appearance of organic solutes in saliva have been in the literature for over 70 years, it has only been in the past 30 years that there has been emphasis on the appearance of drugs. Although many assumptions for drug level monitoring in saliva are made, the primary requisite for salivary monitoring to be useful is a constant or predictable relationship between the drug concentration in saliva and the drug concentration in plasma. Measurement of oral fluid drug levels for the purpose of managing patients and making dosage adjustments may be useful for select drugs or drug classes. However, it does not appear to be useful for the majority of drugs therapeutically monitored. Some work with antipsychotic medications has indicated that although the measurement of drug concentrations themselves may not be useful for dosage adjustment, the ratio of parent drug to metabolite may reflect altered metabolic status due to either pharmacogenetic variation or other clinical conditions. Furthermore, analysis of saliva may provide a cost-effective approach for the screening of large populations.

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Section: Special Applications Of Salivary Drug Levelsmentioning

confidence: 99%

Section: Special Applications Of Salivary Drug Levelsmentioning

confidence: 99%

The Use of Oral Fluid for Therapeutic Drug Management

Langman

2007

Annals of the New York Academy of Sciences

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“…Cytochrome P450 (P450 or CYP) is involved in drug metabolism, but can be divided into many subfamilies, e.g. CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4, each of which is linked to a different set of drugs, and numerous reviews have been published on this topic (8–26). Some drugs, such as S‐mephenytoin, catalysed by CYP2C19 (27–30), and sparteine (31–37), debrisoquine (31–37) and dextromethorphan (38–40), catalysed by CYP2D6, are reported to be affected by pharmacogenetic factors.…”

Section: Introductionmentioning

confidence: 99%

Gender-related differences in pharmacokinetics and their clinical significance

1999

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SUMMARYmay involve differences in physical constitution (body water space, muscle mass, organ blood flow and organ In this review I have attempted to summarize gender function) and physiology (menopause, pregnancy and differences in pharmacokinetics involving the cytomenstruation) between women and men. In addition, chrome P450 (CYP) isozymes of young and mature as hormonal steroid contraceptives are used by some adults, excluding the effects of the menstrual cycle, women, therapeutic drugs for use by pregnant women, use of oral contraceptives and pregnancy. Sex difin particular, should be restricted because of obvious ferences in drug metabolism and elimination are ethical considerations other than age. Thus, the pharmainly related to steroid hormone levels. CYP3A4, macokinetics and pharmacodynamics of many drugs responsible for the metabolism of over 50% of theramay well be different due to a variety of causal factors peutic drugs, exhibits higher activity in women than (Fig. 1). in men. Nonetheless, the absence of a sex difference Cytochrome P450 (P450 or CYP) is involved in drug has been reported by some workers. The activity metabolism, but can be divided into many subfamilies, of several other CYP (CYP2C19, CYP2D6, CYP2E1) e.g. CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4, each of which isozymes and the conjugation (glucuronidation) is linked to a different set of drugs, and numerous activity involved in drug metabolism may be higher reviews have been published on this topic (8-26). Some in men than in women. Drug metabolism in women drugs, such as S-mephenytoin, catalysed by CYP2C19 is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

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“…The βOHC/COR ratio is used to monitor hepatic cytochrome P -450IIIA isoenzyme activity. This enzyme catalyses the oxidation of cortisol and several drugs, including rifampicin, nifedipine, and cyclosporin 25. Increased enzyme activity can be shown by an increase in the βOHC/COR ratio.…”

Section: Discussionmentioning

confidence: 99%

Occupational exposure tocis-1,3-dichloropropene: biological effect monitoring of kidney and liver function

Verplanke

Bloemen²,

Brouwer³

et al. 2000

Occup Environ Med

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Objectives-To investigate the possible eVects of occupational exposure to the nematocide cis-1,3-dichloropropene (cis-DCP) on function of the kidney and liver in the starch potato growing region in The Netherlands. Methods-The study involved 13 commercial application workers exposed to cis-DCP for 117 days, and 22 matched control workers. The inhalatory exposure of the application workers was estimated from biological monitoring data. All workers collected urine and serum samples before, during, and after the fumigation season for monitoring of variables for kidney and liver function. Renal eVect variables were alanine aminopeptidase (AAP), N-acetyl--D-glucosaminidase (NAG), retinol binding protein (RBP), and albumin (ALB) in urine, and 2 -microglobulin ( 2 M-S) and creatinine in serum (Creat-S). Liver variables were alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), -glutamyltranspeptidase (GGT), alkaline phosphatase (ALP), and total bilirubin (TBIL) in serum and the urinary ratio of 6--hydroxycortisol to free cortisol ( OHC/COR). Results-The geometric mean exposure of the application workers was 2.7 mg/m 3 (8 hour time weighted average (8 hour TWA)); range 0.1-9.5 mg/m 3 . No diVerences were found between the values of the renal eVect variables or the liver variables of the exposed group and the control group, except a lower urinary ratio of OHC/COR in the exposed group. This was not considered to be related to the exposure to cis-DCP. No dose-eVect relations were found between the exposure indices and the eVect variables. Conclusions-The present study does not provide evidence that occupational exposure to cis-DCP in the starch potato growing region causes adverse eVects on the kidney or liver at 8 hour TWA exposure concentrations below 9.5 mg/m 3 (2 ppm). ; the DCP fumigants presently available, Telone-cis and Nematrap, consist of more than 95% of the more active isomer cis DCP.In rats, the major route of DCP metabolism is conjugation with glutathione, catalysed by hepatic glutathione transferase. 3 The glutathione conjugate is further metabolised into the mercapturic acid metabolite N-acetyl-S-(cis-3-chloro-2-propenyl)-L-cysteine (cis-DCP-MA). This mercapturic acid metabolite is excreted in urine and is suitable for biological monitoring purposes.1 4 This was confirmed by Brouwer et al. 5Torkelson and Oyen found nephrotoxic and hepatotoxic eVects in rats and guinea pigs exposed to 227 mg/m 3 cis-DCP or trans-DCP, in 19 7-hour exposures for a period of 28 days. 6 Slight to marked eVects on liver and kidney were found in rats and guinea pigs exposed to 50 mg/m 3 DCP, in 27 7-hour exposures for 39 days. Exposure to 14 mg/m 3 for 6 months induced "very slight cloudy swelling of the renal tubular epithelium". However, the eVects in their study were not confirmed by other assays. 7-10In a recent occupational health study, slight nephrotoxic and hepatotoxic eVects were found in application workers exposed to cis-DCP or trans-DCP. In 15 workers exposed to 0.3-9.4 mg/m 3 DCP, increased excre...

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Prediction of Xenobiotic Metabolism by Non‐Invasive Methods

Cited by 13 publications

References 82 publications

The Use of Oral Fluid for Therapeutic Drug Management

The Use of Oral Fluid for Therapeutic Drug Management

Gender-related differences in pharmacokinetics and their clinical significance

Occupational exposure tocis-1,3-dichloropropene: biological effect monitoring of kidney and liver function

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