Biomedical subjects

D G Wilkins

Publications and source records attributed to D G Wilkins.

At least 19 recordsLinked to original sources

PubMed1998

Serum caffeine and paraxanthine as markers for reported caffeine intake in pregnancy.

PURPOSE: Previous studies of maternal caffeine use and pregnancy outcome have relied on self-reported use. Even if these were perfectly accurate, inter-individual differences in caffeine metabolism result in a relatively weak correlation between caffeine intake and serum concentration. The purpose of this study was to determine whether the serum concentration of caffeine or its primary metabolite, paraxanthine, obtained at an unknown time during working hours, is useful to distinguish between pregnant women who report consuming small and large amounts of caffeine. METHODS: We selected from the Birmingham fetal growth study 60 women with normal pregnancy outcomes who reported consuming < or = 0.8 mg/kg/day of caffeine in a 24-hour dietary recall, 60 who consumed 0.81-2.5 mg/kg/day, 60 who consumed 2.51-5.0 mg/kg/day and 59 who consumed > or = 5.01 mg/kg/day. These women had serum drawn for storage during regular clinic hours on the same day as the recall interview. Caffeine and paraxanthine were measured in the stored serum using high performance liquid chromatography. RESULTS: The weighted kappa coefficient between strata of caffeine intake and quartiles of serum paraxanthine was 0.58 among smokers and 0.53 among nonsmokers, versus 0.44 and 0.51, respectively, for quartiles of serum caffeine. The Pearson correlation coefficient between intake and paraxanthine was 0.50 for smokers and 0.53 for nonsmokers, and 0.37 and 0.51, respectively, for serum caffeine. These values are comparable to the correlation between reported smoking and serum cotinine in pregnancy. CONCLUSIONS: The serum concentrations of paraxanthine, and to a lesser degree, caffeine are useful to distinguish between women with varying levels of caffeine intake.

Biomarkers↗

PubMed1998

Incorporation of drugs for the treatment of substance abuse into pigmented and nonpigmented hair.

Hair analysis for drugs may be useful for the long-term monitoring of recidivism and treatment compliance. L-alpha-Acetylmethadol, buprenorphine, and methadone are drugs that are used for the treatment of substance abuse. The purpose of this study was to study the relationship between dose, plasma concentration, hair concentration, and hair pigmentation for these compounds and their major metabolites in an animal model. Male Long-Evans rats received either L-alpha-acetylmethadol (1 and 3 mg/kg; n = 6), buprenorphine (1 and 3 mg/kg; n = 5), or methadone (4 and 8 mg/kg; n = 5) by intraperitoneal injection daily for 5 days. Fourteen days after beginning drug administration, newly grown hair was collected and analyzed for either L-alpha-acetylmethadol and two metabolites (L-alpha-acetyl-N-normethadol and L-alpha-acetyl-N,N-dinormethadol), methadone and two metabolites (D,L-2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium and D,L-2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline), or buprenorphine and one metabolite (norbuprenorphine). The plasma time course (AUC) for each compound was also determined after a single administration of each drug at the specified doses. There was an approximate dose-dependent increase in measured hair concentration of each parent drug in pigmented hair. The concentrations of L-alpha-acetylmethadol, methadone, and buprenorphine in nonpigmented hair were significantly less than that measured in pigmented hair at either the high or low dose. The metabolites L-alpha-acetyl-N-normethadol and D,L-2-ethyl-1,5dimethyl-3,3-diphenylpyrrolinium were detected at lower concentrations than their respective parent compounds (L-alpha-acetylmethadol or methadone) in pigmented hair. However, the L-alpha-acetyl-N,N-dinormethadol metabolite concentrations in pigmented hair were significantly greater than those of the parent drug after either the low or the high L-alpha-acetylmethadol dose. These data demonstrate that L-alpha-acetylmethadol, methadone, buprenorphine, and metabolites are distributed into hair in a dose-related manner with a preference for pigmented hair.

Animals↗

PubMed1998

Simultaneous quantitation of cocaine, opiates, and their metabolites in human hair by positive ion chemical ionization gas chromatography-mass spectrometry.

A sensitive method is developed for the combined extraction of cocaine (COC), cocaethylene (CE), benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NORCOC), 6-acetylmorphine (6-MAM), codeine (COD), norcodeine (NORCOD), morphine (MOR), and normorphine (NORMOR) from human head hair using an enzyme-based digestion technique (Protease VIII/DTT/Tris-buffer pH 6.5 at 22 degrees C). After pH adjustment to 5.5, the digests are extracted with a solid-phase extraction procedure using Bond-Elut Certify columns. The extract residues are evaporated at 40 degrees C, reconstituted in 20 microL of ethyl acetate, and derivatized with the reagents N-methyl-N-trimethylsilylheptafluorobutyramide (MSHFBA), N-methyl-bis-heptafluorobutyramide (MBHFBA), and N-trimethylsilylimidazole (TMSIM). Analyses are performed by positive ion chemical ionization gas chromatography-mass spectrometry using a DB-1 capillary column. Two injections are performed on each extract to optimize sensitivity for all analytes. The assay is capable of reliably quantitating 500 pg/mg of all compounds and is linear to 50 ng/mg, except for BE, which is linear to 25.0 ng/mg. The method was used to analyze human hair samples obtained from cocaine and heroin users. COC, BE, and EME are detectable in all samples, whereas NORCOC, CE, COD, 6-MAM, and MOR are detected in only some samples. Norcodeine and normorphine are not detected. The assay is currently being used to analyze hair samples from a study investigating the mechanisms of drug disposition in hair.

Adult↗

PubMed1997

Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters.

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.

Animals↗

PubMed1997

Detection of alprazolam in hair by negative ion chemical ionization mass spectrometry.

A sensitive and specific method for the quantitative determination of alprazolam (AL) in hair has been developed. After the addition of deuterium labeled triazolam as an internal standard, hair samples (20 mg) were digested with 1 N NaOH at 40 degrees C overnight. Calibrators containing known concentrations of AL dried onto drug-free hair were also prepared and digested. After digestion, the solution was cooled, adjusted to pH 9 with 6 N HCl and 1 ml of saturated sodium borate buffer was added. The digested solutions were extracted with toluene:methylene chloride (7:3) and the organic phase was evaporated to dryness. Extract residues were treated with BSTFA and 1% TMCS and analyzed on a Finnigan-MAT mass spectrometer in the negative-ion chemical ionization mode with methane as the reagent gas. Chromatographic separation was achieved on a Restek-200 capillary column using hydrogen as the carrier gas. The assay was capable of detecting 25 pg/mg of AL and was linear to 250 pg/mg. Intra-assay precision was 11.1% at 25 pg/mg and 5.4% at 150 pg/mg. Inter-assay precision was 11.2% at 25 pg/mg and 5.3% at 150 pg/mg. This method has been used to study the hair incorporation of AL into Long-Evans rats who received 5.0 mg/kg or 7.5 mg/kg i.p. twice a day for 5 days. Preliminary results indicate that the AL concentration in the pigmented and non-pigmented hair on day 14 ranged from 60 to 100 pg/mg.

Alprazolam↗

PubMed1997

A comparison of phenobarbital and codeine incorporation into pigmented and nonpigmented rat hair.

Drugs and endogenous compounds circulating in the blood may ultimately become incorporated into a growing hair shaft. Hair analysis for drugs of abuse is a growing field in the area of forensic and clinical toxicology. However, the underlying principles that govern drug incorporation into hair are not known. In this study, we examined the incorporation of a weak acid, phenobarbital, and a weak base, codeine, into Sprague-Dawley (SD) rat hair. Codeine or phenobarbital was administered to male SD rats at 40 mg/kg/day for 5 days by intraperitoneal (ip) injection. Hair was collected from the back 14 days after beginning the 5-day dosing protocol and analyzed by gas chromatography/mass spectrometry (GC/MS) for codeine and phenobarbital. The time-courses of phenobarbital and codeine in plasma were also obtained after a single ip injection (40 mg/kg). Concentrations of codeine and phenobarbital in SD hair samples were 0.98 +/- 0.10 and 17.01 +/- 1.40 ng/mg hair. respectively. The areas under the curve (AUC) of plasma concentration versus time for codeine and phenobarbital were 1.58 and 414.50 micrograms h/microL, respectively. Notwithstanding the greater phenobarbital concentrations in hair, when plasma concentrations were considered, codeine was apparently incorporated to a 15-fold greater extent than phenobarbital. Because hair pigmentation may be important in drug incorporation, the incorporation of these two drugs was also studied in Long-Evans (LE; produces both black and white hair on the same animal) rats after 40 mg/kg/day of ip drug administration for 5 days. Hair was collected at the same time as the previous experiment. Concentrations of codeine in hair were 44-times greater in pigmented than nonpigmented hair from the same animals. In contrast, hair concentrations of phenobarbital were identical in both pigmented and nonpigmented hair. These data suggest that hair pigmentation greatly affects weak base incorporation but not weak acid incorporation into hair. Because hair concentrations of phenobarbital are not affected by pigmentation, phenobarbital may be an ideal drug to separate out factors other than pigmentation involved in incorporation of drugs into hair.

Animals↗

PubMed1997

Quantitative analysis of l-alpha-acetylmethadol, l-alpha-acetyl-N-normethadol, and l-alpha-acetyl-N,N-dinormethadol in human hair by positive ion chemical ionization mass spectrometry.

A sensitive and specific method was developed for the quantitative analysis of l-alpha-acetylmethadol (LAAM), l-alpha-acetyl-N-normethadol (norLAAM), and l-alpha-acetyl-N,N-dinormethadol (dinorLAAM) in hair. In the development of this method, it was determined that sample pretreatment methods performed by the laboratory greatly affect the measured concentrations of drug and metabolite in hair. Deuterated internal standards were added to 20-mg hair samples and the samples digested overnight in a buffered solution of Protease Type VIII enzyme. Digests were extracted by modification of a liquid-liquid extraction procedure developed previously in our laboratory for the analysis of plasma and tissues. Derivatized extracts were analyzed on a Finnigan MAT 4500 mass spectrometer in positive ion chemical ionization mode using methane and ammonia reagent gases, helium carrier gas, and a DB-5MS (30 m, 0.25-micron film thickness) capillary column. The assay was linear to 50 ng/mg hair (r = 0.99) for all three compounds with a limit of quantitation experimentally determined to be 0.5 ng/mg for LAAM and 0.3 ng/mg for norLAAM and dinorLAAM. Intra-assay precision ranged from 1.0 to 10.5% for the three analytes at concentrations of 0.5, 5.0, and 25.0 ng/mg of hair. Interassay precision ranged from 4.7 to 12.9%. The performance of the method was also evaluated for its utility in detecting and quantitating LAAM, norLAAM, and dinorLAAM in hair from rats (n = 6) that had been administered 3 mg/kg LAAM intraperitoneally once daily for five days. LAAM, norLAAM and dinorLAAM were detectable in pigmented hair at concentrations of 1.27 ng/mg (+/-0.04), 1.28 ng/mg (+/-0.014), and 2.89 ng/mg (+/-0.014), respectively. Five laboratory wash solvents were then evaluated for their effect on the measured concentration of LAAM and metabolites in the rat hair. Phosphate buffer and 1% SDS washes substantially reduced the measured LAAM, norLAAM, and dinorLAAM concentrations by at least 30%, which suggests that drug incorporated into hair is removed (extracted) during the laboratory wash procedures. Wash procedures using methanol, methylene chloride, or water reduced the measured concentrations by no more than 20%. Because measured concentrations of LAAM, norLAAM, and dinorLAAM in hair appear to depend on the specific wash procedures used by a laboratory, quantitative data must be interpreted cautiously based on the sample pretreatment conditions.

Animals↗

PubMed1997

Rapid and reversible effects of methamphetamine on dopamine transporters.

Reactive oxygen species decrease dopamine transporter (DAT) function in vitro. Because of this, and the finding that METH administration causes oxygen radical formation in vivo, the effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection caused a dose-dependent (0-15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after METH administration; an effect attributable to a decreased Vmax of [3H]dopamine uptake. Similarly, multiple high-dose administrations of METH (10 mg/kg/dose; four doses at 2-h intervals) decreased DAT function. The decreases in DAT activity after either single or multiple METH administrations were reversed 24 h after treatment. [3H]5HT transport into striatal synaptosomes was also affected by METH treatment. Taken together, these data suggest that METH decreases DAT activity, perhaps through a reactive oxygen species-mediated mechanism. These findings may have important implications regarding the role of oxidative events in the physiological regulation of monoaminergic systems.

Animals↗

PubMed1997

Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration.

Administration of a single high dose of methamphetamine (METH) causes a rapid and reversible decrease in the activity of the tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine. This effect can be reversed completely by exposing the METH-impaired enzyme to a reducing environment, which suggests that the decrease in TPH activity is a reversible oxidative consequence of free radical formation. Consistent with this hypothesis, a single METH administration to male rats increased oxygen radical formation, as demonstrated by increased striatal dihydroxybenzoic acid formation after coadministration of salicylate with METH. Prevention of METH-induced hyperthermia attenuated both the increase in dihydroxybenzoic acid formation and the decrease in TPH activity observed 1 h after METH administration. These data suggest that both reactive oxygen species and hyperthermia contribute to the acute decrease in TPH activity which results from a single METH administration.

Animals↗

PubMed1996

Determination of alprazolam and alpha-hydroxyalprazolam in human plasma by gas chromatography/negative-ion chemical ionization mass spectrometry.

A sensitive and specific method was developed for the determination of alprazolam and its major metabolite alpha-hydroxyalprazolam in plasma. After the addition of deuterium-labeled internal standards, plasma samples were buffered to pH 9 with 1 ml of saturated sodium borate buffer, extracted with toluene-methylene chloride (7:3) and evaporated to dryness. The residues were treated with N,O-bis(trimethylsilyl)trifluoroacetamide containing 1% of trimethylchlorosilane and analyzed on a Finnigan-MAT mass spectrometer operated in the negative-ion chemical ionization mode with methane as the reagent gas. Chromatographic separation was achieved on a Restek-200 capillary column using hydrogen as the carrier gas. The assay was linear from 0.25 to 50 ng ml-1 for both compounds. The intra-assay precision for alprazolam was 16.1% at 0.5 ng ml-1 and 4.6% at 50 ng ml-1 and that for alpha-hydroxyalprazolam was 15.8% at 0.5 ng ml-1 and 4.2% at 50 ng ml-1. The method was used to determine alprazolam and alpha-hydroxyalprazolam in human plasma samples collected after a single 2 mg oral does of alprazolam. A peak concentration of 32.9 ng ml-1 of alprazolam was detected at 1 h following the dose.

Adult↗

PubMed1996

Codeine disposition in human hair after single and multiple doses.

OBJECTIVE: We studied the dose-proportion and time-course relationships for the incorporation of codeine into human hair after the administration of three different groups. SUBJECTS: Male volunteers, with dark hair, were given oral codeine either as a single dose of 60 mg (n = 7) or 120 mg (n = 12) or as multiple doses of 30 mg 3 times daily for 5 days (n = 7) (450 mg total dose). METHODS: Blood and urine were collected for various times for up to 72 h after dosing. Scalp hair was collected initially by plucking (up to 4 weeks) and later by cutting for up to 10 weeks. Plasma, urine, proximal 1 cm of hair and distal hair were each analyzed for codeine and its metabolites by positive-ion chemical ionization ion trap gas chromatography/mass spectrometry. RESULTS: Codeine was detected in the proximal 1 cm of hair within 30 min of an oral 120-mg dose. Codeine was not detected in the distal hair segment until 3 weeks after receiving a dose of codeine. Codeine was detected in distal hair segments for at least 10 weeks at 30 pg mg-1 hair following a single 120 mg codeine dose and at 90 pg mg-1 hair following 30 mg codeine 3 times a day for 5 days. Morphine or the glucuronides of codeine or morphine were not detected in the hair specimens of these subjects. CONCLUSION: Codeine is rapidly distributed into the germanitive elements of hair in a dose-proportional manner. A portion of the codeine remains bound as the hair grows and can be detected in distal hair for up to 10 weeks after a single dose.

Administration, Oral↗

PubMed1996

Mechanisms for tolerance to methamphetamine effects.

Pretreatment with incremental increases in methamphetamine causes tolerance to serotonergic effects caused by challenging with multiple high doses of methamphetamine (11.5 mg/kg/dose). The brain concentration of methamphetamine following this challenge was reduced in tolerant rats, yet the plasma concentration was elevated. The tolerance was selective for methamphetamine and did not occur when cocaine was used in the pretreatment. The possibility that tolerance affects the distribution of methamphetamine in or out of the brain through an active transport system was examined by combining the transport-blocking drug, probenecid, with a low dose of methamphetamine. The presence of probenecid enhanced methamphetamine-induced serotonergic changes in the hippocampus. The brain concentration of methamphetamine increased in the presence of probenecid; however, a similar increase in the plasma methamphetamine concentration suggests that the effects of probenecid on methamphetamine distribution are not related to the redistribution of methamphetamine that occurs in tolerant animals.

Animals↗

PubMed1996

Detection of stanozolol in hair by negative ion chemical ionization mass spectrometry.

Stanozolol is an anabolic androgenic steroid occasionally abused by athletes. A sensitive, specific, and reproducible method for the quantitative determination of stanozolol in hair has been developed. After the addition of stanozolol-d3 as the internal standard, hair samples (10-25 mg) were digested with 2 mL of 1N NaOH at 65 degrees C for at least 2 h. Digest solutions were then extracted using solid-phase extraction. The eluents were evaporated, a mixture of N-methyl-N-trimethylsilylhepta-fluorobutryamide (MSHFBA) and trimethylsilylimidazole (TSIM) (1000:20, v/v) was added, and the mixture heated at 80 degrees C for 5 minutes. After cooling to room temperature, N-methyl-bisheptafluorobutyramide (MBHFBA) was added and the mixture heated at 80 degrees C for 30 min. The derivatized extracts were analyzed on a Finnigan MATTM 4500 mass spectrometer in the negative chemical ionization mode. Chromatographic separation was achieved with helium carrier gas on a HP-1 capillary column (15 m x 0.2-mm i.d.; 33-microns film thickness). The assay was capable of reliably quantitating 50 pg/mg of stanozolol and was linear to 2500 pg/mg. Intra-assay precision was 13.2% at 50 pg/mg and 6.6% at 2500 pg/mg. Interassay precision was 13.7% at 50 pg/mg and 6.1% at 2500 pg/mg. This method has been applied to the analysis of stanozolol incorporated into rat hair. Male Long-Evans rats were given stanozolol 20 mg/kg intraperitoneally once daily for 3 days. The mean concentrations of stanozolol in the rat hair collected on day 14 were 362.4 +/- 332.4 pg/mg in pigmented hair and 90.0 +/- 46.9 pg/mg in nonpigmented hair. These data demonstrate that stanozolol is incorporated preferentially into pigmented hair.

Amides↗

PubMed1996

Quantitative determination of phencyclidine in pigmented and nonpigmented hair by ion-trap mass spectrometry.

A sensitive and specific method has been developed for the quantitative analysis of phencyclidine (PCP) in pigmented and nonpigmented rat hair. After the addition of PCP-d5 as the internal standard, hair samples (10 mg) were digested overnight in 1N NaOH at 30 degrees C. Digested solutions were then extracted using a solid-phase procedure with Bond Elut CertifyTM extraction columns. Reconstituted extracts were analyzed on a Finnigan ion trap (MagnumTM) mass spectrometer in the electron ionization mode using helium as the carrier gas, and a DB-5 MS (30 m x 0.25-mm i.d.; 25-microns film thickness) capillary column. The assay is linear from 0.1 to 50 ng/mg with a correlation coefficient of > 0.99 and is capable of detecting 25 pg of PCP on column. The accuracy of this assay was estimated using fortified hair standards at PCP concentrations of 0.5 and 10 ng/mg. Intra-assay coefficients of variation were determined to be less than 6% at 0.5, 2, and 10 ng/mg. Interassay coefficients of variation were determined to be less than 15% at 0.5, 2, and 10 ng/mg. The method has been used to evaluate PCP incorporation into Long-Evans rat hair but could also be used to evaluate the incorporation of PCP into human hair. Male rats were shaved prior to dosing such that both pigmented and nonpigmented hair was collected. Animals were administered 12 mg/kg PCP by intraperitoneal injection daily for five days. Fourteen days after the first dose, pigmented and nonpigmented hair were collected and analyzed for PCP. The mean plus or minus the standard error of the mean (n = 5) concentrations of PCP in pigmented and nonpigmented hair were 14.33 +/- 1.43 ng/mg of hair and 0.47 +/- 0.04 ng/mg of hair, respectively. This method is also being used to evaluate PCP as a model xenobiotic for studies of the incorporation of xenobiotics into hair.

Animals↗

PubMed1996

Quantitative analysis of methadone and two major metabolites in hair by positive chemical ionization ion trap mass spectrometry.

A sensitive and specific method for the quantitative determination of D,L-methadone (MD) and its metabolites, D,L-2-ethyl-1,5-dimethyl-3, 3-diphenylpyrrolinium (EDDP) and D,L-2-ethyl-5-methyl-3, 3-diphenyl-1-pyrroline (EMDP), in hair has been developed. Deuterated internal standards of MD, EMDP, and EDDP were added to 20-mg hair samples and digested overnight at room temperature with 1N sodium hydroxide. Calibration standards containing known concentrations of MD, EMDP, and EDDP dried onto human hair were also digested. Digest solutions were extracted by a liquid-liquid extraction procedure and analyzed with splitless injection on a Finnigan MagnumTM ion trap mass spectrometer. Chromatographic separation was achieved with helium carrier gas on a DB-5MS-30M-0.25-micron capillary column. Positive chemicaionization was used with acetone as the reagent gas. The assay was linear from 0.5 ng/mg (MD and EDDP) or 1.0 ng/mg (EMDP) to 50.0 ng/mg of human hair with correlation coefficients greater than 0.99. Intra-assay and interassay coefficients of variation were determined to be less than 20% for all three analytes at 2.0 and 10.0 ng/mg of hair. Recovery was estimated to be greater than 70% (MD and EDDP) and 53% (EMDP) at 2.0 and 10.0 ng/mg of hair. The method has been applied to the analysis of both human and rat hair. Male long-Evans rats were shaved prior to dosing to obtain their drug-free hair. Animals were then administered 15 mg/kg MD by intraperitoneal injection daily for five days. Fourteen days after the first dose, hair was collected and analyzed for MD, EMDP, and EDDP. The mean plus standard error of the mean (SEM; n = 3) concentrations of MD and EDDP in pigmented hair were 31.1 ng/mg +/- 9.6 ng/mg and 8.6 +/- 2.4 ng/mg, respectively. EMDP was detected in the hair of one of three rats. In another experiment, hair was collected from two human subjects who had received long-term methadone therapy for the treatment of heroin addiction. Subject A received 60 mg of methadone daily for at least six months; subject B received 80 mg of methadone daily for at least six months. The hair concentrations of MD were 10.1 ng/mg and 21.0 ng/mg for Subjects A and B, respectively. The hair concentrations of EDDP were 0.5 ng/mg and 2.6 ng/mg for Subjects A and B, respectively. EMDP was not detected in the hair of these two subjects. This method is being used to evaluate the incorporation of MD, EMDP, and EDDP in human and rat hair in dose-response studies.

Animals↗

PubMed1996

Incorporation of codeine and metabolites into hair. Role of pigmentation.

Xenobiotics circulating in the blood may become incorporated into growing hair. Melanin has affinity for many pharmacologically unrelated drugs and is responsible for the pigmentation in hair. To assess the role of pigmentation in the incorporation of drugs into hair, the distribution of codeine and its metabolites was studied in Sprague-Dawley (SD; white nonpigmented hair), Dark Agouti (DA; brown pigmented hair), and hooded Long-Evans (LE; both black pigmented and white nonpigmented hair) rats. Codeine was administered at a dose of 40 mg/kg/day i.p. for 5 days. Fourteen days after beginning the dosing protocol, hair was collected and analyzed for codeine, and its metabolite, morphine, by positive-ion chemical ionization GC/ion-trap MS. The plasma pharmacokinetics for codeine and morphine were also determined after a single 40 mg/kg injection (equivalent to first dose in 5-day dosing protocol) in all three strains of rats. Hair and plasma codeine and morphine concentrations were also determined after acid hydrolysis to evaluate the presence of glucuronide metabolites. Codeine concentrations in the hair of SD, DA, and pigmented LE hair were 0.98 +/- 0.10, 5.99 +/- 1.24, and 111.93 +/- 18.69 ng/mg hair, respectively; morphine concentrations were 0.34 +/- 0.04, 0.51 +/- 0.11, and 14.46 +/- 1.81 ng/mg hair, respectively; morphine glucuronide concentrations were 0.67 +/- 0.08, 1.04 +/- 0.37, and 13.80 +/- 3.60 ng/mg hair, respectively. Studies examining the in vitro binding of [3H] codeine and [3H]morphine to hair demonstrated both specific and nonspecific binding sites for codeine and morphine. Pigmented hair from LE rats possessed the greatest number of binding sites, white hair from SD rats contained the least, and brown hair from DA rats was intermediate. A time course study of codeine and its metabolites showed pigment-mediated differences in incorporation of codeine and metabolites within a few hours of drug administration. These data indicate that pigmented hair possesses a greater capacity to bind and incorporate codeine and its metabolites than does nonpigmented hair. Interpretation of hair concentrations of drugs should involve consideration of hair pigmentation.

Animals↗

PubMed1996

Dose-related distribution of codeine and its metabolites into rat hair.

Drugs and endogenous compounds may be incorporated into the matrix of a growing hair shaft. However, the relationship between incorporation and dose or time course of plasma concentrations is poorly defined. The purpose of this study was to compare plasma and hair concentrations of codeine and its metabolites after various doses of codeine. Male Sprague-Dawley rats had a 1" x 1" square shaved from their backs. Codeine was administered by intraperitoneal injection (10, 20, 40, or 60 mg/kg/day) daily for 5 days. Fourteen days after beginning drug administration, the original patch was reshaved and newly grown hair was analyzed for codeine and morphine using GC/MS. The mean concentrations of codeine in hair for the 10, 20, 40, and 60 mg/kg/day groups were 0.29, 0.57, 0.96, and 1.93 ng/mg hair, respectively, and the concentrations of morphine were 0.15, 0.28, 0.49, and 0.79 ng/mg hair, respectively. The plasma concentration time courses for codeine and morphine were determined after single doses of either 20 or 40 mg/kg. Peak plasma codeine concentrations for the 20 and 40 mg/kg groups were 1,441 and 2,452 ng/ml plasma, respectively, and the areas under the plasma concentration vs. time curve were 699 and 1,581 ng-hr/ml, respectively. Morphine glucuronide, but not codeine glucuronide, was measured in the hair of rats administered codeine. Codeine was also administered to rats by constant intravenous infusion (40 mg/kg/day for 5 days). The concentration of codeine in rat hair after this route of administration was 2.92 +/- 0.72 ng/mg hair. Codeine and morphine are incorporated into rat hair in a dose-proportional fashion. Morphine glucuronide can be found in rat hair after codeine administration. The codeine concentration in hair is the same whether the drug is administered by constant intravenous infusion or daily intraperitoneal injections if the areas under the plasma concentration vs. time curve values are considered.

Animals↗

PubMed1995

The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study.

OBJECTIVE: Our aim was to evaluate prospectively the effects of cocaine and marijuana use on pregnancy outcomes. STUDY DESIGN: A prospective multicenter cohort study was conducted at seven university-based prenatal clinics in the United States from 1984 to 1989. The cohort described herein consisted of a multiethnic population of 7470 pregnant women. Information on the use of drugs was obtained from personal interviews at entry to the study and assays of serum obtained during pregnancy. Pregnancy outcome data (low birth weight [< 2500 gm], preterm birth [< 37 weeks' gestation], and abruptio placentae) were obtained with a standardized study protocol. RESULTS: A total of 2.3% of the women used cocaine and 11.0% used marijuana during pregnancy. Cocaine use was not associated with having a low-birth-weight infant (adjusted odds ratio 0.7, 95% confidence interval 0.4 to 1.3) or a preterm birth (1.3, 0.9 to 2.0). There was no association between short-term exposure to cocaine and preterm delivery (1.1, 0.3 to 4.0). However, cocaine use was strongly associated with abruptio placentae (adjusted odds ratio 4.2, 1.9 to 9.5). Marijuana use was not associated with low birth weight (1.1, 0.9 to 1.5), preterm delivery (1.1, 0.8 to 1.3) or abruptio placentae (1.3, 0.6 to 2.8). By comparison, 35% of the women smoked cigarettes during pregnancy, and cigarette smoking was positively associated with low birth weight (1.5, 1.2 to 1.8). CONCLUSIONS: In this population of women receiving prenatal care, cocaine use was uncommon and was not related to most adverse birth outcomes. Marijuana use was relatively common and was not related to adverse pregnancy outcomes. Tobacco is still the most commonly abused drug during pregnancy, 15% of all cases of low birth weight in this study could have been prevented if women did not smoke cigarettes during pregnancy.

Abruptio Placentae↗