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Caffeine has a shorter duration of effect at high altitude, possibly due to increased blood flow to the liver, and withdrawal from caffeine would likely make altitude problems more severe<ref name="CafAltitude"/>.
=Caffeine clearance=
Caffeine is rapidly absorbed, and its clearance varies with multiple variables, including exercise. It seems that exercise might increase clearance, which in turn might increase the needed dosage for ultra-endurance events. * About 99% of consumed caffeine is absorbed within 45 minutes, with peak concentrations after about 30 minutes<ref name="NehligAlexander2018"/>.* Caffeine half-life is generally 2.5-5 hours with some dose dependency and individual variability<ref name="CamandolaPlick2018"/>.* A study found that lean subjects cleared caffeine faster than the obese, with the half life of 2.6 hours rather than 4.4 hours<ref name="Kamimori-1987"/>.* An hour's light exercise (30% [[VO2max|V̇O<sub>2</sub>max]]) reduced the half life from 4 hours to 2.3 hours in healthy subjects<ref name="Collomp-1991"/>.* A study of 14 active ([[VO2max|V̇O2max]] of 50) subjects (8 women) found no change in caffeine clearance with exercise<ref name="McLeanGraham2002"/>. Subjects exercised for 1.5 hours at 60-65% of [[VO2max|V̇O<sub>2</sub>max]], starting 1 hour after ingesting 6 mg/Kg of caffeine. Half life was ~6 hours. * The half-life of caffeine seems dose dependent<ref name="ChengMurphy1990"/>. In healthy subjects, the half-life at 70mg was 4.5 hours, at 200mg was 60 hours, and at 300mg was 6.4 hours. (Impaired liver function can dramatically increase the half-life to 25-30 hours.)* Caffeine is metabolized by the liver enzyme CYP1A2<ref name="KalowTang1993"/>, and the activity of this enzyme can be effected affected by drugs and diet, with tobacco and chargrilled meat increasing levels<ref name="Flockhart-2007"/>. Things may not be so simple, as about 85% of caffeine is metabolized to Paraxanthine <ref name="GuerreiroToulorge2008"/> and Paraxanthine in mice is a stronger stimulant than caffeine<ref name="Okuro-2010"/>, while similar in humans<ref name="BenowitzJacob1995"/>. Paraxanthine has a half-life of 3.1-4.1 hours<ref name="CamandolaPlick2018"/>, and levels become higher than caffeine after 8-10 hours<ref name="NehligAlexander2018"/> (There is a common genetic mutation in dogs that prevents the formation of CYP1A2, making these dogs unable to metabolize caffeine and some other substances<ref name="AretzGeyer2011"/>.)
=Glucose Absorption, Insulin Resistance and Glycemic index =
Caffeine changes the way glucose is absorbed, but this effect is different for those at rest compared with those exercising.
* A milk intake of 500 to 900 ml/day<ref name="CaffBabyMilk"/>
* The nursing mother's caffeine intake of 200mg/day (one double shot espresso),
We get a resulting caffeine concentration in the milk of 4ug/ml to 8ug/ml<ref name="Stavchansky-"/>, which is a total caffeine intake of between 2mg to 13mg, or 0.6 to 4 mg/Kg body weight. The upper end of that level is quite high. However, the baby's half-life for caffeine is 31-132 hours (average 82 hours)<ref name="Parsons-1981"/>, compared with an adult's 2-10 hour half-life, so the caffeine will build up over time. A 24 hour half live (which is easier to calculate) would result in about a 3mg to 26mg, which is 1 to 8 mg/Kg. I'm guessing that would result in the baby not sleeping well! Conversely, a baby whose mother takes caffeine during pregnancy and is then given formula milk may undergo caffeine withdrawal after birth<ref name="McGowan-1988"/>. Even if the mother breast feeds, the varying levels of caffeine may cause withdrawal symptoms<ref name="Martín-2007"/>. Also, caffeine has been shown to increase fetal [[Heart Rate]]<ref name="Buscicchio-2012"/>. There is research indicating that Caffeine may not reduce to subtherapeutic levels until around 11-12 days<ref name="Doyle-2016"/>.
=References=
<references>
<ref name="Doyle-2016">J. Doyle, D. Davidson, S. Katz, M. Varela, D. Demeglio, J. DeCristofaro, Apnea of prematurity and caffeine pharmacokinetics: potential impact on hospital discharge., J Perinatol, volume 36, issue 2, pages 141-4, Feb 2016, doi [http://dx.doi.org/10.1038/jp.2015.167 10.1038/jp.2015.167], PMID [http://www.ncbi.nlm.nih.gov/pubmed/26562367 26562367]</ref>
<ref name="Martín-2007">I. Martín, MA. López-Vílchez, A. Mur, O. García-Algar, S. Rossi, E. Marchei, S. Pichini, Neonatal withdrawal syndrome after chronic maternal drinking of mate., Ther Drug Monit, volume 29, issue 1, pages 127-9, Feb 2007, doi [http://dx.doi.org/10.1097/FTD.0b013e31803257ed 10.1097/FTD.0b013e31803257ed], PMID [http://www.ncbi.nlm.nih.gov/pubmed/17304161 17304161]</ref>
<ref name="McGowan-1988">JD. McGowan, RE. Altman, WP. Kanto, Neonatal withdrawal symptoms after chronic maternal ingestion of caffeine., South Med J, volume 81, issue 9, pages 1092-4, Sep 1988, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3420441 3420441]</ref>
<ref name="Guest-2018">N. Guest, P. Corey, J. Vescovi, A. El-Sohemy, Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes., Med Sci Sports Exerc, volume 50, issue 8, pages 1570-1578, 08 2018, doi [http://dx.doi.org/10.1249/MSS.0000000000001596 10.1249/MSS.0000000000001596], PMID [http://www.ncbi.nlm.nih.gov/pubmed/29509641 29509641]</ref>
<ref name="snpe_rs76">rs762551 – SNPedia, snpedia.com !!work!!, 18 March 2019 !!access-date!!, [https://www.snpedia.com/index.php/Rs762551 https://www.snpedia.com/index.php/Rs762551]</ref>
<ref name="CamandolaPlick2018">Simonetta Camandola, Natalie Plick, Mark P. Mattson, Impact of Coffee and Cacao Purine Metabolites on Neuroplasticity and Neurodegenerative Disease, Neurochemical Research, volume 44, issue 1, 2018, pages 214–227, ISSN [http://www.worldcat.org/issn/0364-3190 0364-3190], doi [http://dx.doi.org/10.1007/s11064-018-2492-0 10.1007/s11064-018-2492-0]</ref>
<ref name="BenowitzJacob1995">Neal L. Benowitz, Peyton Jacob, Haim Mayan, Charles Denaro, Sympathomimetic effects of paraxanthine and caffeine in humans*, Clinical Pharmacology & Therapeutics, volume 58, issue 6, 1995, pages 684–691, ISSN [http://www.worldcat.org/issn/0009-9236 0009-9236], doi [http://dx.doi.org/10.1016/0009-9236(95)90025-X 10.1016/0009-9236(95)90025-X]</ref>
<ref name="Okuro-2010">M. Okuro, N. Fujiki, N. Kotorii, Y. Ishimaru, P. Sokoloff, S. Nishino, Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice., Sleep, volume 33, issue 7, pages 930-42, Jul 2010, PMID [http://www.ncbi.nlm.nih.gov/pubmed/20614853 20614853]</ref>
<ref name="GuerreiroToulorge2008">S. Guerreiro, D. Toulorge, E. Hirsch, M. Marien, P. Sokoloff, P. P. Michel, Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels, Molecular Pharmacology, volume 74, issue 4, 2008, pages 980–989, ISSN [http://www.worldcat.org/issn/0026-895X 0026-895X], doi [http://dx.doi.org/10.1124/mol.108.048207 10.1124/mol.108.048207]</ref>
<ref name="NehligAlexander2018">Astrid Nehlig, Stephen P. H. Alexander, Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption, Pharmacological Reviews, volume 70, issue 2, 2018, pages 384–411, ISSN [http://www.worldcat.org/issn/0031-6997 0031-6997], doi [http://dx.doi.org/10.1124/pr.117.014407 10.1124/pr.117.014407]</ref>
<ref name="McLeanGraham2002">C. McLean, T. E. Graham, Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women, Journal of Applied Physiology, volume 93, issue 4, 2002, pages 1471–1478, ISSN [http://www.worldcat.org/issn/8750-7587 8750-7587], doi [http://dx.doi.org/10.1152/japplphysiol.00762.2000 10.1152/japplphysiol.00762.2000]</ref>
<ref name="Collomp-1991">K. Collomp, F. Anselme, M. Audran, JP. Gay, JL. Chanal, C. Prefaut, Effects of moderate exercise on the pharmacokinetics of caffeine., Eur J Clin Pharmacol, volume 40, issue 3, pages 279-82, 1991, PMID [http://www.ncbi.nlm.nih.gov/pubmed/2060565 2060565]</ref>
<ref name="Kamimori-1987">GH. Kamimori, SM. Somani, RG. Knowlton, RM. Perkins, The effects of obesity and exercise on the pharmacokinetics of caffeine in lean and obese volunteers., Eur J Clin Pharmacol, volume 31, issue 5, pages 595-600, 1987, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3830245 3830245]</ref>
<ref name="ChengMurphy1990">Wendy S C Cheng, Therese L Murphy, Maree T Smith, W Graham E Cooksley, June W Halliday, Lawrie W Powell, Dose-dependent pharmacokinetics of caffeine in humans: Relevance as a test of quantitative liver function, Clinical Pharmacology and Therapeutics, volume 47, issue 4, 1990, pages 516–524, ISSN [http://www.worldcat.org/issn/0009-9236 0009-9236], doi [http://dx.doi.org/10.1038/clpt.1990.66 10.1038/clpt.1990.66]</ref>
</references>