Juan Antonio Carrillo

Clinically significant pharmacokinetic interactions between dietary caffeine and medications.

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients.The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications.The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy.Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.

Role of the Smoking-Induced Cytochrome P450 (CYP)1A2 and Polymorphic CYP2D6 in Steady-State Concentration of Olanzapine

This study investigated whether the smokinginducible cytochrome P450 (CYP) 1A2 and the polymorphic CYP2D6 play significant roles in the metabolism of olanzapine and its clinical effects at steady-state treatment. Caffeine and debrisoquine were used as measures of CYP1A2 and CYP2D6, respectively. After drug therapy for 15 days, the effect of olanzapine on the activities of CYP1A2 and CYP2D6 was also examined. Seventeen psychiatric patients (9 men and 8 women) were orally administered olanzapine, at a mean ± standard deviation (SD) dosage of 10 mg/d for all smokers (n = 8) and 7.5 ± 2.5 mg/d (range, 5–10 mg) for nonsmokers (n = 9;p < 0.01). The plasma concentration-to-dose (C:D) ratio was closely correlated to the CYP1A2 activity (r s = −0.89;p < 0.0001). The mean urinary caffeine indexes of nonsmokers and smokers were 17 ± 8 and 101 ± 44, respectively, indicating that smoking had induced a sixfold higher CYP1A2 activity (p < 0.0001). Likewise, the olanzapine plasma C:D ratio (ng·mL·mg) was about fivefold lower in smokers (7.9 ± 2.6) than in nonsmokers (1.56 ± 1.1;p < 0.0001). On day 15 of the antipsychotic therapy, the percentage decrease in Brief Psychiatric Rating Scale (BPRS) total score relative to the predosing score (in the drug-free period) was higher for nonsmokers than for smokers (30.4 ± 10% vs. 12.5 ± 14%;p < 0.01). Six nonsmokers and three smokers experienced side effects with olanzapine. After 15 days of drug treatment, olanzapine had caused significant (p < 0.0001) and substantial CYP1A2 inhibition (by 50%) in comparison with predosing values, and such inhibition can contribute to adverse drug interactions. In conclusion, smoking-induced increased CYP1A2 activity significantly diminished plasma olanzapine concentrations and the antipsychotic effect of the drug. The performance of a simple caffeine test may assist in individualization of the olanzapine dosage.

Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity

Fluvoxamine is a selective serotonin reuptake inhibitor used widely in the treatment of depression and other psychiatric diseases, but little is known about the specific isozymes involved in its metabolism. This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hydrocarbon (as contained in cigarette smoke) inducible CYP1A2.

Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva and urine.

Twenty-five healthy volunteers were given 100 mg caffeine orally and several estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The validation was performed by correlation of different parameters in plasma, saliva, and urine to two measures of caffeine clearance, CL(oral) and CL(137X-->17X) that served as standards of reference. Two subjects were excluded because of noncompliance with a caffeine-free diet. In the remaining 23 subjects, both plasma and saliva total clearances of caffeine were highly correlated with each other (r(s) = 0.97, p < 0.0001). The ratio 17X/137X restricted to one sampling point taken 4 hours after dose, showed a high correlation (r(s)) with CL(oral) and CL(137X-->17X) in plasma (0.84/0.83) and saliva (0.82/0.77) (p < 0.0001 for all the correlation values) where 17X is 1,7-dimethylxanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Additionally, the ratio (AFMU + 1U + 1X + 17U + 17X)/137X in a 0-24 hours urine sampling showed the highest correlation with CL(137X-->17X) (r(s) = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1-methyluracil, 1X is 1-methylxanthine, and 17U is 1,7-dimethyluric acid. The major estimates of CYP1A2 activity were significantly less in nonsmoking females, and this probably was related to the use of oral contraceptives in this subpopulation. In summary, among caffeine-based approaches for CYP1A2, the authors recommend either plasma or saliva 17X/137X ratio and the urinary (AFMU + 1U + 1X + 17U + 17X)/137X ratio during a sampling interval of at least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activity to be used in the study of human populations.

Low daily 10‐mg and 20‐mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19)

Fluvoxamine is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 and the smoking‐inducible CYP1A2. Therapeutic doses of fluvoxamine inhibit both CYP1A2 and CYP2C19. In this study we used extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin (INN, debrisoquine) (CYP2D6) and two probes, caffeine (CYP1A2) and omeprazole (CYP2C19), to investigate whether nontherapeutic doses of fluvoxamine inhibit CYP1A2 but possibly not CYP2C19.

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

Summary.The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers.The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation.Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers.The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.

Caffeine metabolism in a healthy Spanish population: N‐Acetylator phenotype and oxidation pathways

We studied the oxidative and N‐acetylator caffeine metabolic profile in 107 healthy Spanish volunteers. Smokers had significantly higher N‐1‐ and N‐3‐demethylations activities than nonsmokers (p = 0.03 and p = 0.02, respectively), and the three caffeine demethylations indexes were strongly correlated with each other (r > 0.7; p < 0.001). Our in vivo studies suggest that CYP1A2 is involved, at least in part, in the primary N‐demethylations of caffeine. A non‐normal and possibly bimodal distribution was detected in the xanthine oxidase activity (p = 0.04), with about 4% of subjects deficient of this metabolic activity. The population exhibited a trimodal distribution of acetylator phenotype determined by use of the 5‐acetylamino‐6‐amino‐3‐methyluracil/1‐methylxanthine ratio (normality test; p = 0.004). Seventy subjects (65.4%) were phenotyped as slow acetylators. The mutated gene frequency was 0.81, which is similar to other white populations.

Effects of Caffeine Withdrawal From the Diet on the Metabolism of Clozapine in Schizophrenic Patients

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: An interaction study with fluvoxamine and ketoconazole as in vivo inhibitors

Potential drug‐drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3‐hydroxyropivacaine and (S)‐2′,6′‐pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine.

Potential role of cerebral cytochrome P450 in clinical pharmacokinetics: modulation by endogenous compounds.

Cytochrome P450 (CYP) enzymes catalyse phase I metabolic reactions of psychotropic drugs. The main isoenzymes responsible for this biotransformation are CYP1A2, CYP2D6, CYP3A and those of the subfamily CYP2C. Although these enzymes are present in the human brain, their specific role in this tissue remains unclear. However, because CYP enzymatic activities have been reported in the human brain and because brain microsomes have been shown to metabolise the same probe substrates used to assess specific hepatic CYP activities and substrates of known hepatic CYPs, local drug metabolism is believed to be likely. There are also indications that CYP2D6 is involved in the metabolism of endogenous substrates in the brain. This, along with the fact that several neurotransmitters modulate CYP enzyme activities in human liver microsomes, indicates that CYP enzymes present in brain could be under various regulatory mechanisms and that those mechanisms could influence drug pharmacokinetics and, hence, drug response.In this paper we review the presence of CYP1A2, CYP2C9, CYP2D6 and CYP3A in brain, as well as the possible existence of local brain metabolism, and discuss the putative implications of endogenous modulation of these isoenzymes by neurotransmitters.